Chapter 4: Chronic Stress Pushes Our Brains into Survival Mode

“If indeed the hippocampus is impaired and the amygdala facilitated by stress, it would suggest the possibility that stress shifts us into a mode of operation in which we react to danger rather than think about it. It’s not clear whether this is a specific adaptation or whether we’re just lucky that when the higher functions break down our fallback position is one in which we can let evolution do the thinking for us.”

-Joseph LeDoux

Chapter Summary:

This article delves into why prolonged psychological stress, characterized by elevated cortisol levels, triggers a cascade of detrimental changes in the mammalian brain, notably in the hippocampus and prefrontal cortex (PFC). These changes, encompassing hypometabolism and reduced synaptic density, are posited to be part of a neuroecological program—a sophisticated biological response evolved to adapt behavior in mammals under adverse conditions. The article puts forth three hypotheses to elucidate this phenomenon:

Firstly, it suggests that chronic stress acts as a signal, indicating a life-threatening environment. This signal prompts the brain to dial down the activity in regions like the PFC, which have the capacity to inhibit the stress response axis. Essentially, it’s as if the brain decides that in a high-risk scenario, it’s more important to focus on immediate survival rather than on complex, long-term planning.

Secondly, the hypothesis posits that stress denotes an unpredictable environment where higher-level cognitive processes might be less effective. In such scenarios, the brain might shift its reliance more towards instinctual, defensive behaviors governed by the lower brain regions. This shift reflects an evolutionary strategy prioritizing immediate, reactive responses over elaborate, thought-out actions in uncertain situations.

Lastly, the article explores the idea that prolonged stress signals that complex events are difficult to systemize using delayed associations. Consequently, there’s a decreased need for the PFC to maintain contextual, task-relevant information over extended periods. This implies a shift away from the PFC’s role in sustaining long-term strategies and plans, adapting instead to a more immediate, moment-to-moment mode of operation.

The article further expands on the idea that humans, much like other vertebrates, exhibit adaptive responses to chronic stress across various systems, including metabolic, cardiovascular, and neuroendocrine functions. It proposes that this adaptability extends to the cerebral cortex, mediating a transition from a time-intensive, explicit, and controlled processing of information to a more rapid, implicit, and automatic mode. This shift in information processing, from explicit to implicit, represents an evolutionarily ingrained mechanism, enabling mammals, including humans, to effectively navigate and survive in environments laden with stress and uncertainty.

The Mental Effects of Chronic Stress Defined:

The stress cascade is a series of physiological changes that occur in response to prolonged, intense stress. This is known as chronic stress, which occurs when the body experiences stressors with such frequency or intensity that the autonomic nervous system does not have an adequate chance to activate the relaxation response on a regular basis. When the body remains in a constant state of anxiety stress hormones produce well-orchestrated physiological changes that can have long-term effects on physical and psychological health.   Unfocused thinking and difficulty concentrating Memory problems Brains areas associated with higher intellectual function are damaged Anxiety, Depression, Irritability, Mood swings Persistent feeling of pressure and overwhelm

The Brain’s Adaptive Responses to Stress

Organisms throughout the five kingdoms can modify their body type to better conform to their environment (Auld et al., 2010). Some of these changes are transient and reversible, whereas some are comprehensive and permanent. The studies of phenotypic plasticity and “predictive, adaptive responses” have shown that virtually all species can be reprogrammed by portending environmental cues, that the changes are brought about by alterations in gene expression, and that they allow conformation to occasional but regularly recurring environmental pressures (DeWitt & Scheiner, 2004). These alternate environments typically involve stressors that demand different body types, behaviors, and reproductive tactics (Pigliucci, 2001).

Often the adaptive response to stress is conserved within groups of related organisms that inhabit similar ecological niches (Via & Lande, 1985). For instance, even though all organisms respond plastically to nutrient/energy deprivation, mammals exhibit a unique suite of physiological changes aimed at lowering the metabolism of specific organ systems in the interest of continued survival (Wells, 2009). This chapter will discuss phenotypic changes in mammalian brain structure in response to stress. These well-documented brain changes, and the resulting behavior, are characterized as potentially adaptive responses to adverse ecological scenarios. Different lines of converging evidence will be considered in an exploratory and expository manner.

The mature mammalian brain can be reshaped by prolonged stress in two primary ways: 1) metabolic activity, dendritic growth, and memory function are enhanced in the brain’s fear centers (i.e., the amygdala and caudate nucleus), and 2) metabolic activity, dendritic growth, and memory function are reduced in the higher learning centers (i.e., the hippocampus and prefrontal cortex (PFC)) (Cohen et al., 2007; Sapolsky, 2003). Stress’s effects on neural circuitry are mediated by the stress hormone cortisol, which activates the numerous cortisol receptors in the amygdala, hippocampus, and PFC (Morales-Medina et al., 2009). Once activated, these receptors trigger pathways that result in the expression or silencing of particular genes. These genes are responsible for the neurological remodeling (Petronis, 2000, 2004; DeWitt & Scheiner, 2004). This remodeling may help stressed mammals adapt to environmental adversity, with its particular threats and opportunities.

In the scientific literature, the responses to stress in the amygdala and basal ganglia have been attributed adaptive significance (Sapolsky, 2003). However, the changes in the hippocampus and PFC have mostly eluded the attention of evolutionary biologists (Reser, 2007). In other words, scientists have realized that it probably helps stressed mammals to be more wary and reactive. Increased activity in the amygdala is thought to help animals become more sensitive and responsive to threats (Radley & Morrison, 2005). Neural and dendritic growth in the amygdala enables animals to identify stressors and mobilize the body to address them (Sapolsky, 2003) by increasing heart rate, breathing rate, and adrenaline (Roozendaal et al., 2009).

A different way to increase activity in the amygdala is to release it from the structures that suppress it (Mitra & Sapolsky, 2008). The PFC and hippocampus have long been identified in neurology as brain regions capable of inhibiting emotional responses to fear-inducing stimuli (Cannon, 1929; Papez, 1937; MacLean, 1949; LeDoux, 1987). This circuitry ensures that mammals can override the fear response if they determine that the stimulus may appear threatening but is not actually threatening (Morgan et al., 1993). Diminishing activity in the PFC and hippocampus may ensure that the areas that incite stress can function unimpeded during stressful times.

Decreased activity in the PFC and hippocampus may also adaptively influence the animal to be more impulsive (Reser, 2007). When facing lasting adversity, it may be advantageous to suppress the PFC and hippocampus because these areas put inhibitory pressure on defensive, instinctual, and dominant responses. When an animal experiences extreme stress, its behavioral strategies are likely proving relatively ineffective (Boonstra, 2005). It may benefit such an animal to be less reliant on learned behavior and more reliant on instinctual behaviors. Hence, the hippocampus and PFC changes may protectively disinhibit innate urges (Reser, 2007).

This chapter will elaborate on three complementary hypotheses: 1) stress signifies that the prevailing environment is antagonistic and that the animal should not suppress the stress response or inhibit conditioned fears; 2) stress signifies that behaviors that the animal has learned may be inefficacious and that it should increase its reliance on innate behaviors over learned behaviors; and 3) stress indicates that environmental events are proving difficult to understand on long time scales and thus contextual, task-relevant information in the PFC need not be maintained for temporally-extended periods.

Table 1 describes the general psychological consequences of the brain changes to be discussed, as well as the implications they have for modern people and theoretical implications they may have had for prehistoric foragers. This table highlights that today we find these changes limiting, but they may have been helpful in the prehistoric past.

Table 1

The Psychological and Neurological Effects of Stress, Then and Now

Neurological State	Psychological Consequences	Implications for Moderns	Implications for Foragers
Amygdala hyperactivity	Potentiation of learned fears	Anxiety, fear, and excessive stress	Healthy caution, preparedness, and mobilization
Caudate hyperactivity	Potentiation of unconscious, habitual movements	Intrusion of habitual responses	Increased reliance on movements that have been proven effective
PFC hypoactivity	Behavioral disinhibition	Working memory and goal-setting problems	Increased reliance on instinctual and appetitive impulses
mPFC hypoactivity	Impaired inhibition of learned fears	Exaggerated stress responses to nonfatal threats	Enhanced awareness of potentially fatal threats
Hippocampal hypoactivity	Inaccessibility of contextual memories	Explicit / declarative memory problems	Increased reliance on dominant and procedural responses

Interestingly, early-life stress causes a pattern of changes strikingly similar to the changes that occur in response to chronic stress in adulthood (Weinstock, 2008). When pregnant rodent or primate mothers are stressed, they program highly analogous changes in their offspring’s amygdala, hippocampus, and PFC (Francis et al., 1999; Kapoor et al., 2006; Schneider et al., 1999).

The behavioral changes in these offspring, which include increased vigilance, fearfulness, and stress responsivity, have been interpreted by Michael Meaney and colleagues as constituting a predictive and adaptive response to early environmental adversity (Zhang et al., 2006). In this interpretation, the amygdalar changes are attributed adaptive qualities. Moreover, psychiatric disorders such as anxiety, depression, posttraumatic stress disorder, and schizophrenia are associated with prenatal and postnatal stress and involve the same pattern of changes to the hippocampus, PFC, and amygdala (Axelson, 1993; Corcoran, 2001).

Elevated levels of noradrenaline and dopamine, such as occur during acute yet transient stress, impair working memory and attention regulation but strengthen fear learning, habitual behaviors, and reflexes (Elliot & Packard, 2008; Packard & Teather, 1998). Thus, acute stress, chronic stress, prenatal stress, and a number of major psychiatric disorders have all been shown to engineer a switch from thoughtful “top-down” control to unthinking “bottom-up” control (Buschman & Miller, 2007; Hermans et al., 2014). This chapter will focus on these cortical corollaries of pronounced stress and attempt to interpret them in terms of their ecological utility to mammals, from wild rodents to prehistoric humans.

If the neurological changes in response to stress were diffuse or only degenerative, this might indicate that they do not represent adaptation. That the alterations are very selective, that they completely spare critical cortical and subcortical regions, that there are dozens of documented molecular pathways that converge toward these changes (Stankiewicz et al., 2013), and that neural activity in the amygdala (Francis et al., 1999; Radley & Morrison, 2005; Vyas et al., 2003) and caudate (Kim et al., 2001; Schwabe et al., 2008) is actually enhanced, suggests that these changes may not be pathological. To further explore the proposed evolutionary rationale for why these changes might constitute an adaptive response, we turn to the neurobiology of stress perception.

How Animals Perceive and Respond to Stressful Stimuli

The recognition of an immediate physical stressor often takes place in the amygdala. On the other hand, the recognition of a delayed or abstract stressor occurs in the cerebral cortex (Bremner, 1999; LeDoux, 1998). The “low” and more direct pathway in the amygdala (sensory receptors to thalamus to basolateral amygdala to PVN) allows the animal to respond quickly to dangerous stimuli before it can consciously assess the situation (Dbiec & LeDoux, 2009). The high and more circuitous cortical pathway is around twice as slow (around 24 milliseconds (at its fastest) as opposed to 12 milliseconds). This is because it passes through the cortex, which is informed by higher learning centers that allow context and formal thought to tailor the response (Pessoa & Adolphs, 2010). Quite often, the cortical route serves to subdue or inhibit the amygdala’s response to stress (Quirk et al., 2003). The fact that the cortex can suppress the stress response may make it beneficial in a safe environment. However, in an adverse environment, its potential to convey false security may amount to an unjustifiable liability.

The amygdala, hippocampus, cortex, and several other areas of the brain have extensive connections to the hypothalamus, the brain center responsible for initiating the stress response (Bremner, 1999). Even transient signals from these areas (induced by fear, horror, or helplessness) can induce the PVN of the hypothalamus to secrete adrenaline and corticotropin-releasing hormone (CRH), which act throughout the brain, especially in the hypothalamus and the locus coeruleus (Dedovic et al., 2009). Both adrenaline and CRH affect cognition, stimulating anxiety and fear-related behaviors (Gold, 2005).  If the stressor lasts long enough or if the CRH levels are sufficiently high, the release of adrenocorticotrophic hormone (ACTH) is triggered within the pituitary, which induces the release of glucocorticoids (GCs) by the adrenal cortex (Lovallo & Gerin, 2003). Cortisol, the GC in humans (rodents have corticosterone), moderates the physiological response to chronic or lasting stressors by inducing an array of effects throughout the body (Mastorakos et al., 2005).

The natural variation in stress reactivity seen in animals is thought to reflect niche adaptation and be associated with individual differences in a range of life history-relevant domains including: affiliation, competitive risk-taking, parental investment, self-regulation, somatic effort, reproductive functioning and learning (Ellis et. al., 2006).

The frequency and duration of stress exposure are thought to carry predictive information about environmental unpredictability and violent death. A heightened stress system is thought to enhance performance during stress-provoking or life-threatening situations (Wingfield et al., 1998) and facilitate fearfulness, vigilance, and cautiousness. These traits would have been highly adaptive during extended periods of dire stress (Marks and Nesse, 1994). Chronic stress initiates up-regulation of the hypothalamic-pituitary-adrenal axis (HPA) in rodents, primates, and humans, causing the stress response to become more pronounced and more easily triggered (Miller & O’Callaghan, 2002; Sapolsky et al., 1986; Lovallo & Gerin, 2003). This lasting up-regulation is thought to be an adaptation to sustained environmental demand (Petronis, 2000).

Furthermore, enhanced reactivity of the amygdala enables the animal to react to every seemingly threatening stimulus as if it were a full threat. This will inevitably lead to false alarms, but in terms of reproductive success, it is clearly better to overreact to a nonthreat than to underreact to a genuine threat (Nesse & Young, 2000). That the amygdala becomes hyperactive during prolonged stress has already been attributed adaptive significance (LeDoux, 1996). How can the changes in the hippocampus and the PFC be understood? In the academic literature, the role of the hippocampus and the PFC in contributing to this behavioral response has been neglected.

How the Hippocampus is Modified by Stress

The response to acute stress, mediated by adrenaline, and the response to prolonged stress, mediated by cortisol, increase energy use in the brain, heightening both memory and processing speed. However, when cortisol levels are sufficiently high, the opposite occurs, and energy usage in some brain areas can be cut drastically (Foy et al., 2005). After about 30 minutes of intense stress, this “inverted U” relationship becomes apparent, and PFC and hippocampus-dependent mental functions begin to decline (Alexander et al., 2007; Dolcos & McCarthy, 2006; Luethi et al., 2009; Liston et al., 2009; Sapolsky, 1994). In fact, if the cortisol levels are elevated over many hours, neurodegenerative processes commence in the forebrain, primarily in the hippocampus and PFC (Kim & Yoon, 1998; Zhu et al., 2007). Hippocampal volume is known to decrease in response to prolonged environmental stress in rodents, monkeys, humans, and presumably most other mammals (Lambert & Kinsley, 2004). The damage to the hippocampus can progress to the point of neuron loss, apoptosis, and memory impairment in humans and across mammalian species (McEwen, 2007). This wide taxonomic susceptibility makes the hippocampal neurodegenerative response to stress appear to have been naturally selected and conserved.

The hippocampus, an area within the medial temporal lobe of the brain, plays the role of the modulator of the hypothalamic-pituitary-adrenal response to stress. It does so by inhibiting the actions of the hypothalamus. The PVN of the hypothalamus receives extensive inhibitory collaterals from the hippocampus (Radley & Morrison, 2005). Activity in the PVN can be both tonically and phasically overridden by these inhibitory inputs (Mitra et al., 2005). The hippocampus has many cortisol receptors, is very sensitive to fluctuations in cortisol levels, and is well-suited for its job of creating negative feedback for CRH release (Diorio, 2000). When blood cortisol concentrations reach sufficiently high levels, the hippocampus sends inhibitory messages through its projections to the PVN of the hypothalamus, signaling that the stress response has gone on for too long and must be diminished (Bao et al., 2007). However, lasting elevations of cortisol are toxic to the hippocampus and lead to volume reduction as well as hippocampal dysfunction (Kim & Yoon, 1998). Decreased volume of the hippocampus results in a diminished ability to generate negative feedback on cortisol release. This is a driving element in the lasting, autocatalytic potentiation of stress known as the “stress cascade” (Sapolsky, 1996).

The high-affinity mineralocorticoid receptors for glucocorticoids, when activated, serve to enhance learning and LTP, whereas the low-affinity glucocorticoid receptors (which are ten times more difficult to bind to and are only occupied heavily during major stressors) strongly inhibit both LTP and primed burst potentiation (PBP) (de Kloet et al., 2005; Herbert et al., 2006). When the glucocorticoid receptors are activated heavily, their occupancy leads to the prolonged opening of calcium-dependent potassium channels resulting in decreased neuronal excitability (McEwen & Sapolsky, 1995). Prolonged GC elevations have been shown to lead to excitotoxicity, cytoarchitectural damage, the inhibition of neurogenesis, and atrophy of dendritic branch points in the CA1 and CA3 cell fields of the hippocampus (Sapolsky, 2003). Apart from the hippocampus and PFC, other brain areas are not insulted by stress in this way. Why not? It is certainly possible that these changes are truly pathological and maladaptive and that they occur due to some currently unknown tradeoff, where the neurons retain some advantage despite an accompanying susceptibility to cortisol. However, given that hippocampal degeneration liberates activity in the PVN of the hypothalamus, the response may alternatively represent an effort to reduce apathy in the face of threat. This process can be seen as complementary to the neuroproliferation in the amygdala.

Aside from inhibiting the hypothalamus, the hippocampus is also crucially involved in encoding and retrieving declarative or explicit memory, including episodic (contextual) and spatial memories (Eichenbaum, 2004). Moreover, chronic stress is known to impair episodic (otherwise known as hippocampus-dependent) memory (Diorio, 2000; Sapolsky et al., 1986), which is central to high-level mental functioning. Why should both functions share the susceptibility to neurodegeneration? Could it be because episodic memory plays a role in inhibiting defensive responses? Perhaps episodic memory provides information about when not to be afraid but is also subject to making fatal errors. Perhaps during adversity, the animal should not trust hippocampal inhibitory schemas based on isolated autobiographical events but should instead act on general, semantic knowledge (averaged over many autobiographical events) held in early/lower cortical areas. As it happens, the area of the PFC that is most extensively connected with the hippocampus – the medial prefrontal cortex (mPFC) – is thought to mediate hippocampal-dependent aspects of episodic memory, is instrumental in suppressing the stress response, and is also the cortical area damaged the most by chronic stress (Quirk et al., 2003).

How the PFC is Modified by Stress

It is widely accepted that the mPFC has a commanding capacity to diminish the stress response (Figueiredo et al., 2003). In fact, the amygdala receives extensive inhibitory collaterals from the PFC (Radley & Morrison, 2005). Like the hippocampus, the mPFC is a target of both acute and repeated stress (Cerqueira et al., 2007). For instance, acute stress from social speaking has shown to diminish cognitive flexibility, the regulation of attention, and working memory (Luethi et al., 2009). Also, emotionally upsetting movies have been associated with significantly reduced PFC activation. Neuroimaging work has demonstrated that acute stress negatively affects working memory-related activation of the dorsolateral PFC (Qin et al., 2009). Chronic stress leads to dendritic retraction and debranching in many areas throughout the PFC in rodent and primate models (Brown et al., 2005; Patel et al., 2008). The volumetric reductions in rat mPFC due to stress are confined to the upper layers, where most hippocampal projections terminate (Jay & Witter, 1995). Synaptic density has also been shown to be significantly diminished in various PFC regions, including the mPFC and dorsolateral PFC (Radely et al., 2006). Interestingly, data indicate that neurons in the rat infralimbic PFC that project to the amygdala do not lose dendritic material in response to stress (Shansky et al., 2009), highlighting the distinct preservation of amygdala circuits. Interestingly, as in the hippocampus, PFC dendritic damage interferes with the ability of the mPFC to suppress the stress response (Mizoguchi et al., 2003).

In rodents, even short intervals of stress can reverse the extinction of fear conditioning (resulting in the resurrection of old fears), which is thought to be caused primarily by stress dysregulation of the mPFC (Izquierdo et al., 2006). Cell fields of the mPFC attenuate emotional responsiveness by directly inhibiting the basolateral amygdala (Figueiredo et al., 2003). Regions of the mPFC also inhibit the stress response by acting on the hypothalamus indirectly through the hippocampus (Mizoguchi et al., 2003). The PFC is connected to the hippocampus by axons originating in the subiculum and ventral CA1 subfields (the same cell field that shows the most pronounced dendritic atrophy during chronic stress). These efferents travel from the hippocampus through the fimbria-fornix system and terminate in glutamatergic contacts with pyramidal cells and interneurons of the mPFC (Liston et al., 2006). The connections between these two areas are thought to modulate both learning and memory processes. They also regulate the stress response, ultimately through inhibition of the release of corticotrophin-releasing hormone (CRH) in the PVN of the hypothalamus (Cerqueira et al., 2007). That these affected areas are both involved in explicit memory, stress diminution, and the stress cascade is probably not coincidental.

Modern cognitive neuroscience has identified conflicts of interest between the cortex and the amygdala, where they often contradict and even inhibit one another (McEwen, 2007). In fact, the cortex tonically inhibits the amygdala, and only when a fear stimulus is very powerful can the amygdala override the suppressive effects of the cortex (LeDoux,1996). Many studies, including research with humans, have shown that the mPFC, especially the ventromedial PFC (vmPFC), plays a significant role in inhibiting defensive and emotional responses (Phelps, 2004).

Fig 1. Anatomical location of the amygdala, PFC, mPFC, and vmPFC.

To extinguish fear behaviors, the vmPFC suppresses amygdala function by engaging a network of inhibitory interneurons that synapse on the amygdala (Sotres-Boyen et al., 2004). The vmPFC is also the subsection of the mPFC that exhibits the greatest reduction in activity in response to chronic stress (Koenigs & Grafman, 2009). Studies have shown that rats with lesions in the vmPFC continue to act fearful in the presence of discontinued, conditioned fear stimuli long after rats without lesions learned to ignore these stimuli (Morgan et al., 1993; 2003; Morgan & LeDoux, 1995). Destruction of the vmPFC abolishes the ability to suppress fears and causes animals to react fearfully to fear-conditioned stimuli, even if they are vastly reduced in intensity (Milad & Quirk, 2002). It seems that natural selection “acted” on this phenomenon and selected the mPFC (especially the vmPFC) to be susceptible to chronic stress for functional reasons.

Inhibiting Stress Reactivity is Maladaptive in a Hostile Environment

In a safe environment, the explicit processing of the hippocampus and PFC is likely beneficial because it helps the animal to draw inferences about, systemize, and understand complex environmental variables. This is a time-intensive process that involves creating and testing hypotheses. In a safe environment, faulty associations or examples of unwarranted inhibition are not punished heavily. Explicit processing may take the emphasis away from threat and allow the animal to pursue things that it finds rewarding and interesting. In an unsafe environment, though, an animal should be less concerned with secondary and tertiary reinforcers and instead focus on food, sex, and survival, relying on age-old, instinctual behaviors that are less susceptible to error.

The basolateral amygdala bases its decisions (whether to incite stress or not) on implicit, nondeclarative, and acontextual memories (Fanselow & Gale, 2006). This suggests that the amygdala is essentially a co-occurrence detector. The amygdala warns us based on simple associations without respect to how, where, when, or why (Eichenbaum, 2004). In contrast, the cortical-hippocampal complex employs explicit memories that use context and episodic events to make inferences about uncertain details (Manns & Eichenbaum, 2006; Labar & Cabeza, 2006; Reber, 2008). This type of inferential thinking must be susceptible to all the pitfalls and hazardous heuristics of cognition identified by cognitive psychologists (Kida, 2006; Todd & Gigerenzer, 2000).

The memories for co-occurrences that exist in the PFC, relative to those in the amygdala, involve higher-order associations because they involve neurons capable of sustained firing (Goldman-Rakic, 1995). Neurons in the PFC can span a wider delay time or input lag between associated occurrences (Zanto, 2011). Proximity in time (temporal contiguity) between two stimuli is not necessary for them to become associated. Thus, PFC processing can involve subjective inferences about causality based on prior experience. The response properties of neurons in the amygdala; however, limit the amygdala to encoding information about the objective association of two, near simultaneous events (LeDoux, 1996). Therefore, the amygdala is susceptible to making false alarms and misses. However, the hippocampus and cortex can formulate associations (from inductive reasoning) that are illusory and not representative of valid relationships in the environment.

How Stress Modifies the Dopamine System

The mesocortical dopamine system is heavily impacted by stress. Both acute and chronic stress have been shown to dysregulate dopamine transmission in the ventral tegmental area VTA (Patel et al., 2008). In contrast, the mesolimbic system (activated by situations requiring motivation and physical effort) is not adversely affected by stress. Acute stress is associated with increases in dopamine levels, excessive dopamine receptor (D1 and D2) stimulation (Vijayraghavan et al., 2007Gibbs & D’Esposito, 2005), and accompanying reductions in sustained firing and optimal tuning of PFC neurons (Vijayraghavan et al., 2007). This effect has been observed in humans (Gibbs & D’Esposito, 2005) and other mammals (Druzin et al., 2000).

The case is similar for chronic stress. Whereas elevated levels of glucocorticoids increase dopaminergic transmission in the mesocortical system in the short-term, long-term elevations in GCs decrease dopaminergic transmission causing comparable reductions in sustained firing and correct tuning of PFC neurons (Mizoguchi K et al., 2000). This has been taken to underlie the “inverted-U” relationship between working memory and stress (Gibbs & D’Esposito, 2005), mirroring that seen in hippocampus-dependent memory.

Dopamine sent from subcortical VTA neurons modulates the activity and timing of neural firing in the PFC, acting to sustain ongoing neural activity. Dopamine neurotransmission in the PFC is thought to be instrumental in the ability to internally maintain and update contextual information. Seamans and Robbins (2010) suggest that the DA/PFC system may play a major role in how attentional resources are allocated to understand the meaning of patterns of stimuli and the strategies to cope with or take advantage of them. It is essential for mammals to capture information about unexpected occurrences so they can identify systematic patterns within them. This effort must be focused on the contextually unique features of the novel scenario. For this to happen, those features must be maintained in working memory through sustained firing over elapsing time so that the cognitive modeling taking place can analyze their significance.

Chronic stress reduces sustained firing in PFC neurons. We can expect that this reduces the frequency of associations made between temporally distant stimuli. Perhaps this is because, during stressful times, associations made between temporally distant stimuli may lead to misinformed or ineffective behavior. Interestingly, neurons in the vmPFC have been shown to be instrumental in the tendency to falsely perceive coherent patterns in random events (Clark,  2010). Perhaps in adverse environments it is less helpful to search memory for relationships between stimuli that occur in delayed succession and instead to focus on those occurring in quick succession. The dopaminergic dysregulation may also suggest that chronic stress takes emphasis from top-down modeling and instead places emphasis on bottom-up responses.

Inhibiting Instinctual Impulses is Maladaptive in a Hostile Environment

The hippocampus and especially the PFC, are involved in inhibiting innate and instinctual drives other than fears, and the neurodegeneration that takes place in these areas in response to stress may adaptively disinhibit reliable and valuable impulses (Reser, 2007; Wirth, 2015). Highly encephalized vertebrates, like mammals, can inhibit impulses, delay gratification, and prolong anticipation when it is clear that this will be beneficial in the long run. Mammals and primates in particular, employ this kind of restraint to wait for an opportunity, deceive a competitor, cooperate or reciprocate with a conspecific, submit to a dominant individual, or acquiesce to their own offspring (Kappeler & van Schaik, 2006). When times are difficult, resources are sparse, and predators are numerous, restraint and deference are probably ineffective tactics (Wilson, 2000). In the wild, when times are tough, temperance, discipline, hesitation, and forethought may often be handicaps.

Neurodegeneration in the PFC and hippocampus caused by stress are known to create deficits in executive function, learning, and memory (Arnsten, 2009). For instance, in rats, LTP disruption in the hippocampus-mPFC pathway, which significantly impairs working memory, can be induced after only a single episode of acute stress (Rocher et al., 2004). Chronic stress-induced dendritic atrophy in the mPFC has been shown to correlate with severe functional deficits in attentional control and higher-order cognitive function (Liston et al., 2006). These deficits in working memory and executive function have been speculated to be maladaptive in the literature because they reduce representational flexibility and preparatory set (Cerqueira et al., 2007). This is undoubtedly true, but working memory probably involves costs in addition to its advantages. For example, working memory allows the generation of alternatives to innate tendencies. Overriding innate tendencies can be adaptive or maladaptive, ultimately depending on context.

The PFC is notorious for suppressing urges from lower, instinctual regions. It sends projections to many subcortical areas, allowing mammals to inhibit the things that come naturally (Fuster, 2009). Humans constantly inhibit lower-order drives. For example, it is largely thought that anorexia nervosa is an example of the frontal lobe suppressing the hunger drive created by lower brain centers like the hypothalamus (Spinella & Lyke, 2004). Hunger is a fundamental instinctual drive that, at least in humans, can be vastly overridden by PFC function. Clearly, the cortex can formulate its own plans and use its inhibitory capacities to create behavior at odds with reproductive success.

The hippocampus is probably also involved in inhibiting innate behavior, even if indirectly. The first functional conceptualization of the hippocampus claimed that it was an area responsible for “behavioral inhibition” (Nadel et al., 1975). Since then, the focus has moved to its importance in spatial abilities and episodic memory, but there is still a good deal of evidence that it is involved in inhibiting impulses. For instance, animals with hippocampal damage tend to be hyperactive and have difficulty learning to inhibit previously reinforced responses (Best et al., 1999). Thus, the neurodegenerative changes within the hippocampus in response to stress might also result in behavioral disinhibition.

In contrast, amygdala activation causes an animal to neglect what it was thinking about earlier, arresting its ongoing activity and orienting it to a new stimulus (Morgan, 1993). Animals with amygdalar lesions are less responsive to external stimuli and are predisposed to internal stimulation (Kandel et al., 2000). This may be why stress causes the amygdala to become hyperactive and the hippocampus and PFC to become hypoactive: stress signifies that the focus should be on the external world, not the inner world.

The neurodegenerative effects of chronic stress may be revolting against a hidden danger, the “tyranny” of the prefrontal cortex. Hyperfrontality is a nonclinical but documented syndrome characterized by excessive prefrontal domination of behavior. Hyperfrontal individuals can be stoic, reserved, obsessive, repressive, neurotic, detached, and dispassionate. They quell and override subcortical impulses by mobilizing past learning and beliefs. This behavior can surely be adaptive but probably only in specific ecological contexts. Hyperfrontality and hypofrontality may represent opposite strategies on a behavioral continuum that have been maintained through natural selection (environmental heterogeneity). The hypofrontality seen in traumatized individuals and in those with schizophrenia or PTSD (Buchsbaum, 1991) may be an effort to reduce tyrannical prefrontal supervision, making them less “susceptible” to temporally distant or conceptually abstract rewards such as taking the steps they need to attain a raise or promotion. Patients with prefrontal damage engage in behaviors aimed at immediate gratification (like binge eating or committing crimes) even though they can appreciate that the long-term results of their actions are often self-defeating (Eslinger et al., 2004). Perhaps during adversity in the ancestral past, behaviors aimed at immediate gratification were not as self-destructive as they often prove to be today.

It is important to point out that what the PFC and hippocampus allow animals to inhibit is often what their genes are “recommending.” The brainstem, along with the diencephalic and limbic areas, is hard-wired with many ethologically appropriate responses engendered by natural selection over geological time (hundreds of millions of years). Environmental stimuli constantly activate these inclinations, and in lower animals, this almost always results in outward behavior. In animals with large cortices, though, the subcortical predispositions are merely suggestions, not commands, because they can inhibit them and try something more complicated.

Motivational impulses originate subcortically (e.g., midbrain reticular formation and hypothalamus), and are sent via the anterior thalamus to higher structures (e.g., amygdala, cingulate cortex, PFC, and hippocampus), which provide feedback regulation that may reinforce or inhibit the generation of the impulse. Some of the projections carrying this feedback travel directly to the originating structures, while others regulate the ascending subcortical inputs through the thalamus by way of the pallidum. This process may involve the well-known cortico-striato-pallido-thalamic loop (Swerlow & Koob, 1987). PFC and hippocampus-dependent, explicit memory determines what this feedback to the subcortex will be and provides the behavior that may supplant the subcortical recommendations. If the environment is barbaric and irrational, then perhaps contrived and complicated behavior is less adaptive than time-tested, instinctual behavior. This seems especially true when one considers that explicit behaviors require much more processing time before a reaction can occur.

Chronic Stress, Reaction Time, and the Basal Ganglia

Several well-received studies have found that acute stress biases processing toward caudate-dependent learning strategies (Kim et al., 2001) and improves performance on habitual and well-rehearsed tasks (Broadbent, 1971; Wickens et al., 2007). In humans and rodents, chronic stress has been associated with a substantial decrease in the use of hippocampal-dependent learning strategies and a dramatic increase in the use of caudate-based learning strategies (Schwabe et al., 2008; Hartley & Adams, 1974; Packard & Cahill, 2001). This stress-induced shift from top-down, explicit information processing to automatic, implicit processing has been well characterized experimentally (Packard & Wingard, 2004). Many researchers have concluded that this is because stress impairs PFC operation but spares ingrained habits dependent on the basal ganglia, as well as late motor and early sensory cortices (Arnsten, 1998; Elliot & Packard, 2008). Robert Sapolsky, a leading researcher of stress neuroscience, has concluded that the stress cascade may adaptively recalibrate the brain to emphasize regions responsible for habitual or procedural responses, such as the caudate nucleus (1994).

Humans under intense chronic stress have been shown to exhibit potentiated reflexes and increased speed for habitual movements (Pfaffman & Schlosberg, 1930; Vasterling et al., 2006; Vedhara et al., 2000). Combat veterans with PTSD, especially those using the caudate heavily in life-threatening situations (such as riflemen), exhibit hypertrophic caudate nuclei and atrophic hippocampi (Bremner, 1999). Since the processes of the hippocampal and caudate systems work antagonistically at times (Voermans et al., 2004), hypoactivity in the hippocampus and PFC may permit subcortical movement areas more autonomy and ensure that the thinking mind cannot easily interfere with their responses.

Reaction time, or the delay between the input and output seen in an animal’s behavior, is an indication of the amount of neural processing taking place, where more processing equates to longer delays (Bogacz et al., 2009). The least encephalized animals have the fastest responses (Chittka et al., 2009). For example, animals such as insects display reaction times that are hundredths of those observed for mammals (Dean, 2005). In fact, reaction time slows with the number of synapses interposed between input and output (Kandel et al., 2000). The neurodegenerative effects of stress on the PFC likely act to adaptively potentiate instinct but may also speed up the reaction to the environment as it is known that explicit movements trade speed for informedness.

The Hippocampus can be Adaptively Modified in Many Mammals

Behavioral strategies based on hippocampal learning probably work well in a predictable and ordered environment. An environment that sends clear, honest signals about the interrelationships between complex variables allows animals to formulate ecologically meaningful knowledge. Chaotic and violent environments, however, may not be amenable to hippocampal-based strategies. In a stressful environment, many of these signals are probably muddled and misleading. Clinical psychologist George Kelly has argued that in a stressful or anxiety-provoking environment, it is usually challenging for humans to understand the critical variables and how they interrelate (1991).

Figure 3.1 Human Memory Hierarchy.

Stress is known to be exacerbated when the human or rodent cannot figure out how to make things better, feels helpless, or feels like it has no control (Glass et al., 1971; Minor et al., 1984). In fact, an experimental animal subjected to numerous stressors will liberate significantly less cortisol if it is made to think that it has some control over the frequency of the stressors, even if it does not actually have any control (Sapolsky, 1994). If the animal has little control over its environment, why should it expend energy attempting to make sense of it? Top-down regulation of behavior may only be beneficial for reproductive success if the animal can use its systemizations to exert meaningful control. When environmental variables are incomprehensible, and the animal has little influence over them, then explicit thinking may be as extraneous as it is in less encephalized animals, precisely because there is no “correct solution” for higher cognition to arrive at.

The glucocorticoid stress hormones generally cause different tissues and organ systems to put off long-term, expensive building projects. These include growth, digestion, tissue repair, sexual reproduction, and immune function. They do this to redirect the body’s energy toward fighting and flight. In much the same way, PFC and hippocampal-dependent learning (unlike caudate and amygdalar learning) are slow and cumulative processes that represent long-term efforts at informing behavior in the distant future (Eichenbaum, 2004). If supply lines toward provident but expensive long-term somatic efforts are cut off when cortisol is elevated, it seems sensible that the long-term mental efforts would also fall into this category. Hippocampal-dependent memory, in the sense that it is contextual and episodic, represents new, untested learning. For this reason, relative to other brain areas, it may be expendable in adverse situations.

Notably, there are other examples of natural selection favoring altered processing priorities, and these also involve neurodegeneration. The study of neuroecology has shown that hippocampal size can vary dramatically in individual animals over the course of a single season. In fact, neuronal fluctuations in the hippocampus are known to occur in various food-caching mammals (Kemperman, 2002) and birds (Garamszegi & Eens, 2004). The hippocampus increases significantly in volume during seasons when the animal must remember where it hid its food and then decreases when the season ends (Clayton, 2001). Neurogenesis in the hippocampi of individual adult mammals is known to increase with environmental stimulation and enrichment (Kemperman, 1997; 1998) and decrease along with the diminishment of body size, metabolic rate, and need to forage (Jacobs, 1996). This relationship between environmental demand and investment in hippocampal neurons is commonly interpreted as an ecological strategy focused on the tradeoff between saving energy and reliance on hippocampus-dependent memory (Dukas, 2004). The similarities here suggest that the stress cascade, which occurs in a wide variety of animals, may also be an example of a neuroecological response.

Stress, Cognition, and Evolutionary Medicine

Researchers in the field of evolutionary medicine view stress and anxiety as adaptive when they permit animals to effectively escape danger (Marks & Nesse, 1994). It has been shown that animals that have a genetic susceptibility to being highly stressed or anxious are more likely to avoid being eaten by predators (Dugatkin, 1992). Williams and Nesse (1998) have pointed out that a proclivity for enhanced stress responsiveness may be highly beneficial in terms of reproductive success, especially in adverse environments. In fact, it is widely accepted that diverse animal species use the neuroendocrine stress axis to integrate sensory input regarding habitat quality to inform the appropriate level of fear, withdrawal, avoidance, paranoia, and other defensive behaviors (Meaney et al., 2000).

Articles written in evolutionary medicine have examined clinical syndromes such as anxiety, posttraumatic stress disorder (PTSD), and depression and characterized them as beneficial responses to dangers such as predator pressure, scarcity, and conspecific conflict (Baron-Cohen, 1997). Each of these disorders has been hypothesized to respond to different ecological scenarios. Depression has been conceptualized as a permissive strategy that emphasizes the appeasement of dominant individuals and low risk-taking (Allen & Badcock, 2006). Anxiety is considered a careful, cautious strategy where fears and aversive drives are emphasized over appetitive drives (Marks & Nesse, 1994). PTSD has been conceptualized as a threat-avoidant strategy where the individual is particularly sensitive to stimuli it found traumatic in the past (Panksepp, 2006).

These and other psychological disorders may represent compartmentalized suites of psychophysiological symptoms that become adaptive in particular environmental contexts. Many “behavioral syndromes” have been discovered in mammalian species. These are thought to represent adaptive responses to particular scenarios, despite appearing maladaptive when taken out of their ecological context (Sih et al., 2004). There is an emerging consensus now in ethology that when traits are correlated, they should be studied together as an ecological package rather than as isolated units (Sih et al., 2004).

The three major traits of the stress cascade, cortisol dysregulation, reduced hippocampal volume, and impairment in hippocampus-dependent memory, are also major components of depression, anxiety disorders, PTSD, and schizophrenia (Lambert & Kinsley, 2004). Moreover, these four disorders are linked with prolonged stress, past traumatic experience, exaggerated stress response, PFC dysregulation, attentional deficits, startle potentiation, and increased heart rate responsivity (Corcoran, 2001; Axelson et al., 1993). Disorders like schizophrenia, PTSD, anxiety, and depression could perhaps each represent behavioral syndromes that employ the defensive benefits of the stress cascade, as identified in this chapter. See Table 2 below.

Table 2

The Neurological Effects of Stress Associated with Different Conditions

Condition	Hippocampus Hypoactivity	PFC Hypoactivity	Amygdala Hyperactivity
Acute Stress	de Kloet et al., 2005; Herbert et al., 2006; Elliot & Packard, 2008;	Rocher et al., 2004; Patel et al., 2008;	Radley & Morrison, 2005; Roozendaal et al., 2009
Chronic Stress	Kim & Yoon, 1998; Lambert & Kinsey, 2004	Liston et al., 2006; Zhu et al., 2007	Francis et al., 1999; Radley & Morrison, 2005; Vyas et al., 2003
Prenatal Stress	Weinstock, 2008; Schneider et al., 1999	Francis et. al., 1999; Kapoor et al., 2006	Zhang et al., 2006; (Meaney et al., 2000)
Anxiety Disorder	McEwen, 2007	Price et al., 2011	Francis et al., 1999; Nutt, 2001; Vyas et al., 2003
Depression	Lambert & Kinsley, 2004	Corcoran 2001; Axelson et al., 1993	Siegle et. al., 2006
PTSD	Bremner, 1999	Liberzon & Sripada, 2007	Panksepp, 2006
Schizophrenia	Tamminga et al., 1992; Bilder, 1995	Andreasen et al., 1997; Carter et al., 1998; Goldman-Rakic, 1999	Grace, 2000

Evolutionary perspectives regard diseases as adaptations that are no longer beneficial because of a “mismatch” between the ancestral and modern environments (Williams & Nesse, 1998; Neel, 1999). In modern times, the cognitive repercussions of excessive stress impair our ability to function professionally and decrease our quality of life in the workplace and at home, even though our stressors are rarely life-threatening or even physical. Because of this mismatch, the stress cascade (and associated disorders) appears to be out of place in time, yet another example of an “ecological anachronism.”

Discussion

After an exploratory review of relevant literature, this chapter concludes that the three hypotheses presented in the introduction cannot be accepted or rejected but have been met with supporting evidence. In addition to the benefits of disinhibiting the stress response and defensive and evasive responses, the stress cascade may also allow the animal to disinhibit appetitive drives and help it to be opportunistically nearsighted. Perhaps during stressful times, PFC functions such as the temporal organization of behavior, inhibition of spontaneous activity, long-term goal setting, and flexibility regarding novelty all take a back seat to the more primal cognitions involving brainstem impulses, hypothalamic inclinations, limbic drives, and striatal urges.

Delaying gratification, thinking twice, and creating elaborate mental models of one’s environment may be unattractive modes of operation during stressful times when it may be better to employ Occam’s razor and simplify, streamline, and expedite. The PFC and hippocampus strong-arm behavioral control of the animal from its hard-wired instincts to the beliefs and associations that the animal fabricated based on its unique and eccentric interactions with the world. These may give the animal means to subdue, pervert, and incapacitate the prime directives of nature.

Table 3

Features of the Stress Cascade that are Interpreted in an Evolutionary Context

• Wide taxonomic susceptibility with highly conserved features
• Dozens of molecular pathways that converge toward the neurological changes
• A high degree of neuroanatomical specificity in the hippocampus and PFC, both within and between species
• Most brain areas are completely spared
• Some brain areas are up-regulated rather than down-regulated
• Neural remodeling resembles known neuroecological changes
• Acute stress, chronic stress, and prenatal stress share neuropathological symptomatology
• Anxiety disorder, depression, PTSD, and schizophrenia also share these symptoms
• Enrichment, stimulation, and maternal care have opposite effects on the hippocampus and PFC

Richard Dawkins (1976) has argued that the cortex has not been allowed totalitarian autonomy over behavior in any species because such animals would develop motivations that are inconsistent or conflicting with the motives of their genes. Dawkins points out that the highly evolved human mind allows us to temporarily escape the direction of “selfish” genes by allowing us to reprogram and even override our instinctive behavior. Today humans can choose not to have children or to commit suicide, decisions few animals are granted the authority to make. Humans have this degree of “free will” because their ancestral ecological niche was highly cognitively demanding and necessitated ingenuity, insight, tolerance, and restraint. However, evolution only allows animals intellectual abilities to the extent they will help them to survive and pass on their genes. When we take a “gene’s eye view” of the stress cascade phenomenon, it becomes apparent that our “selfish” genes are not “concerned” with our higher-order intellectual abilities. Despite their contributions to consciousness and selfhood, hippocampus-dependent explicit memory and PFC-dependent working memory are expendable from a gene’s perspective when these abilities interfere with the propagation of germ cells.

Episodic memory (hippocampal-dependent) and working memory (PFC-dependent) may have matured under relatively favorable circumstances over the last 300 million years. These two forms of memory may have been pioneered mainly in early mammals during the Mesozoic and then expanded in primates during the Cenozoic to inhibit and modify lower impulses and fears in accordance with what the animal has come to know or believe (Dunbar & Shultz, 2006). The sizeable frontal lobe in primates makes it so that subcortical structures participate in but do not dominate the decision-making process (though during panic, they may (Panksepp, 1998)).

The economic concept of discounted future returns comes into play here. Individuals that discount future returns highly, care more about the returns they will receive today, but not those they will receive next year. This person wants immediate gratification and, for example, might cross an ally for a meal today. Some one that does not discount future returns, will be very focused on planning for the future and maximizing prospects for tomorrow, next week, and next year. They will share with a potential ally in an attempt to strengthen a bond that may reap rewards later.

Primates have a voluminous and richly connected frontal lobe because their environments require a tremendous capacity to learn and integrate. The slow process of “cortical refinement” that has taken place over the last several hundred thousand years has allowed the human brain to develop further. Our PFC allows us to be self-disciplined, polite and reserved – strategies that are probably only apposite during times of civility. When the environment cannot be rationalized, however, implicit, procedural, caudate, and amygdalar behavioral strategies may be preferable to explicit, declarative, and cortical ones. That even humans have this vulnerability says something very specific about the adaptive value of intelligence. The hypothesized benefits of this vulnerability are listed in table 4 below.

Table 4

Hypothesized benefits of hippocampal and PFC neurodegeneration during stress

• Reduced inhibitory pressure on the amygdala and PVN
• Increased reaction time and disinhibition of lower motor centers
• Increased innate, instinctual, and species-specific behaviors
• Increased defensiveness, withdrawal, avoidance, vigilance, and opportunism
• Increased resistance to delayed gratification, temporal discounting, and delayed or abstract rewards
• Stress may signify that higher-order strategies are failing or perceiving false patterns
• Untested episodic memories may be tenuous during times of stress
• Associations between temporally distant stimuli maybe tenuous during times of stress

It will be difficult to determine irrefutably if what we know as the stress cascade was in fact, an adaptive process in the ancestral past. The hypotheses presented here are largely exploratory and rely on convergent, comparative evidence. This is partly due to the paucity of related research. Furthermore, the present chapter has made some unsupported assumptions about stress ecology and the nature of advanced cognition in the wild. However, this type of exploratory analysis is generally thought to be progressive as it is thought that analyzing disease states from an evolutionary perspective may ultimately do much to inform and influence medical theory, clinical research, and ultimately even intervention strategies.

One way to test or falsify the present hypotheses would be to expose animals to artificial but ecologically valid environments and assess their behavior. Rats reared in a stress-free, enriched, and nurtured environment could be analyzed relative to rats that have been stressed pre and post-natally. Both groups could be introduced into an environment high in predation, social defeat, or low in resources. The ability of each group to negotiate the stress-filled environment, avoid threats and attain reproductive success could be quantified and compared, and the specific hypotheses listed in Table 4 could be tested. A different way to test these hypotheses would be to look for allelic or phenotypic variants in low-stress populations. For example, the glucocorticoid receptor in mammals found on islands without natural predators could be expected to exhibit lower binding affinity or present in the hippocampus in lower density because of their inhibitory effects on learning (LTP). Mineralocorticoid receptors, which favor LTP, might be expected to exhibit the opposite. Furthermore, comparative molecular techniques may be able to resolve polymorphic alleles that show evidence of a selective sweep, balanced polymorphism, or other distinctive signatures of positive selection. Detailed knowledge of this type of natural variation could help inspire effective pharmacological or gene therapy treatments for humans.

The evolutionary and comparative perspectives delineated here could potentially provide structure for empirical investigations in behavioral ecology or psychiatric research. Molecular phylogenetic analyses should be able to determine if the analogs of the stress cascade in other mammals are actually homologous to those in humans and trace the evolution of the relevant genes. Better knowledge of the shared molecular pathways and neural circuits involved will provide a framework for therapies aimed at ameliorating neuropsychiatric symptoms and the more subtle, everyday effects of stress on human cognition.

Chapter Summary

• Prolonged psychological stress increases the levels of the stress hormone cortisol, which in turn reduces metabolic rate and synapse density in the hippocampus and the prefrontal cortex (PFC).
• This chapter evaluates and explores evidence supporting the hypothesis that these effects of prolonged stress constitute an adaptive program that modifies behavior in mammals experiencing adverse conditions.

• Humans and countless other species of vertebrates have been shown to make predictive, adaptive responses to chronic stress in many systems, including metabolic, cardiovascular, neuroendocrine, and even brain systems (amygdalar and striatal).

• It is proposed in this chapter that humans and other mammals may also have a brain-based response to pronounced stress that mediates a transition from complex thinking to simplified thinking.

• This takes the animal from time-intensive, explicit (controlled/attentional/top-down) information processing to quick, implicit (automatic/preattentive/bottom-up) processing.

• Three complementary hypotheses are proposed: 1) chronic stress signifies that the prevailing environment is life-threatening, indicating that the animal should decrease activity in brain areas capable of inhibiting the stress axis; 2) stress signifies that the environment is unpredictable, that high-level cognition may be less effective, and that the animal should increase its reliance on defensive, procedural and instinctual behaviors mediated by lower brain centers; and 3) stress indicates that environmental events are proving challenging to systemize based on delayed associations, and thus the maintenance of contextual, task-relevant information in the PFC need not be maintained for temporally-extended periods.

Stress Cascade

The autonomic nervous system (ANS) is a phylogenetically ancient mechanism for preparing animals to act adaptively in response to environmental stress. Not all species of animals have an ANS though. It is thought that passive, sessile, filter feeders like corals, sea squirts and anemones do not have stress response systems because, like plants, they are not ambulatory. Even some motile animals though are without an ANS such as jellyfish, combjellies and their kin (cnidarians and ctenophores). Animals as different from us as insects have primitive but functional ANSs (Miller, 1997). We share a common ancestor with insects, and other arthropods, over 590 million years ago yet some functions of the ANS have been conserved. The vertebrate ANS that we are familiar with; however, with the characteristic cytoarchitecture, the ganglionic structures, the sympathetic / parasympathetic division, the preganglionic neuronal columns and various projections to glands, has only been around since our lineage developed jaws (Ghysen, 2003).  

In humans there are two anatomically but functionally integrated stress response circuits: the corticotropin-releasing hormone system and the locus coeruleus-norephineprine (NE) system. The corticotropin-releasing hormone system consists of the HPA axis and amygdala circuitry. Whereas the locus coeruleus-NE system consists of noradrenergic cells of medulla and pons and projections to amygdala, hippocampus, mesolimbic dopamine system and the MPFC.

Hans Selye (1978) underadaptation (insufficient response to stress) and overadaptation (excessive response to stress). Neuroticism vs. Psychoticism (Lester, 1981). Electrodermal activity, heart rate, blood pressure, startle. Why the variability? – Genepool variation

Another thing that might be happening is the damage to the hippocampus and the frontal lobes may be affecting the same kind of change advised by eastern religion. Buddhism and other religions that advocate meditation teach novices to focus on the present for prolonged periods so that they can reduce anxiety about the present and past. Most worrying involves obsessions about the past or future and living in the present keeps one centered in reality instead of on the imagination. Perhaps humans and rats both use the cortex to model past and forthcoming events to prepare and perhaps this decreases their attentiveness to reality. Perhaps when stress is high the adaptive value of this kind of modeling decreases, “living in the present” is the best strategy for a mammal.

The reaction to stress indicates the failure of mammalian intelligence.  Negative environmental feedback in the form of stress, cues predictive of maternal deprivation, and nutritional deprivation all elicit adaptive neuropathological changes that attempt to recapitulate a reptilian cognitive strategy.  Remember the hippocampus is part of the neomammalian limbic system. 

Mention that in theoretical physics a lot of emphasis is taken from empirical findings and put on theory, involving mathematics. If you can prove it with mathematics, but you cant yet test it in the field it, you can still publish. In biology we use the algorithm of evolution, and the comparative biology as well, you make sure that your theory can be supported on these grounds is like building a mathematical model. The reason for this is because the higher order concepts in biology are irreducible cannot be quantified in the way that they can in physics.

There is an inverted-U effect whereby a modest DA increase facilitates cognition and a large increase disrupts it. At low to moderate concentration DA enhances postsynaptic responses, whereas at higher concentrations it can depress them. This accords with the Yerkes-Dodson principle of the relationship between arousal and performance. Importantly there may not be an “optimal” level. What is optimal may depend on the cognitive function or the behavioral paradigm being tested. At optimal levels , D1 receptor stimulation preferentially suppresses the delay related firing to nonpreferred directions and this is thought to reduce noise. Higher D1 stimulation such as occurs during stress, suppresses all delay-related firing. 

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