Seeding Stress Resilience through Inoculation.

Stress is a generalized set of physiological and psychological responses observed when an organism is placed under challenging circumstances. The stress response allows organisms to reattain the equilibrium in face of perturbations. Unfortunately, chronic and/or traumatic exposure to stress frequently overwhelms coping ability of an individual. This is manifested as symptoms affecting emotions and cognition in stress-related mental disorders. Thus environmental interventions that promote resilience in face of stress have much clinical relevance. Focus of the bulk of relevant neurobiological research at present remains on negative aspects of health and psychological outcomes of stress exposure. Yet exposure to the stress itself can promote resilience to subsequent stressful episodes later in the life. This is especially true if the prior stress occurs early in life, is mild in its magnitude, and is controllable by the individual. This articulation has been referred to as "stress inoculation," reminiscent of resilience to the pathology generated through vaccination by attenuated pathogen itself. Using experimental evidence from animal models, this review explores relationship between nature of the "inoculum" stress and subsequent psychological resilience.

Stress coping stimulates hippocampal neurogenesis in adult monkeys.

Coping with intermittent social stress is an essential aspect of living in complex social environments. Coping tends to counteract the deleterious effects of stress and is thought to induce neuroadaptations in corticolimbic brain systems. Here we test this hypothesis in adult squirrel monkey males exposed to intermittent social separations and new pair formations. These manipulations simulate conditions that typically occur in male social associations because of competition for limited access to residency in mixed-sex groups. As evidence of coping, we previously confirmed that cortisol levels initially increase and then are restored to prestress levels within several days of each separation and new pair formation. Follow-up studies with exogenous cortisol further established that feedback regulation of the hypothalamic-pituitary-adrenal axis is not impaired. Now we report that exposure to intermittent social separations and new pair formations increased hippocampal neurogenesis in squirrel monkey males. Hippocampal neurogenesis in rodents contributes to spatial learning performance, and in monkeys we found that spatial learning was enhanced in conditions that increased hippocampal neurogenesis. Corresponding changes were discerned in the expression of genes involved in survival and integration of adult-born granule cells into hippocampal neural circuits. These findings support recent indications that stress coping stimulates hippocampal neurogenesis in adult rodents. Psychotherapies designed to promote stress coping potentially have similar effects in humans with major depression.

Acute corticosterone treatment is sufficient to induce anxiety and amygdaloid dendritic hypertrophy.

Stress is known to induce dendritic hypertrophy in the basolateral amygdala (BLA) and to enhance anxiety. Stress also leads to secretion of glucocorticoids (GC), and the BLA has a high concentration of glucocorticoid receptors. This raises the possibility that stress-induced elevation in GC secretion might directly affect amygdaloid neurons. To address the possible effects of GC on neurons of amygdala and on anxiety, we used rats treated either acutely with a single dose or chronically with 10 daily doses of high physiological levels of corticosterone (the rat-specific glucocorticoid). Behavior and morphological changes in neurons of BLA were measured 12 days after the initiation of treatment in both groups. A single acute dose of corticosterone was sufficient to induce dendritic hypertrophy in the BLA and heightened anxiety, as measured on an elevated plus maze. Moreover, this form of dendritic hypertrophy after acute treatment was of a magnitude similar to that caused by chronic treatment. Thus, plasticity of BLA neurons is sufficiently sensitive so as to be saturated by a single day of stress. The effects of corticosterone were specific to anxiety, as neither acute nor chronic treatment caused any change in conditioned fear or in general locomotor activity in these animals.

Prefrontal-hippocampus plasticity reinstated by an enriched environment during stress.

Chronic stress causes dendritic atrophy of neurons within the hippocampus and medial prefrontal cortex. In this report, we show that chronic stress leads to reduced long-term potentiation in the pathway from the hippocampus to the medial prefrontal cortex of rats; and that such reduction is rescued by enriched housing environment. Connectivity between the hippocampus and medial prefrontal cortex is proposed to be an essential substrate that is often compromised in several psychiatric disorders. Our observations suggest that a short period of complexity in the housing environment has the potential to protect the functional integrity of this important connection.

Cardinal role of the environment in stress induced changes across life stages and generations.

The stress response in rodents and humans is exquisitely dependent on the environmental context. The interactive element of the environment is typically studied by creating laboratory models of stress-induced plasticity manifested in behavior or the underlying neuroendocrine mediators of the behavior. Here, we discuss three representative sets of studies where the role of the environment in mediating stress sensitivity or stress resilience is considered across varying windows of time. Collectively, these studies testify that environmental variation at an earlier time point modifies the relationship between stressor and stress response at a later stage. The metaplastic effects of the environment on the stress response remain possible across various endpoints, including behavior, neuroendocrine regulation, region-specific neural plasticity, and regulation of receptors. The timescale of such variation spans adulthood, across stages of life history and generational boundaries. Thus, environmental variables are powerful determinants of the observed diversity in stress response. The predominant role of the environment suggests that it is possible to promote stress resilience through purposeful modification of the environment.

Environment and early life: Decisive factors for stress-resilience and vulnerability.

Early life is a critical and sensitive period whereby environmental imprints on later life are generated. These environmental influences from early life have long-lasting consequences on for mental health. Both human and animal work suggests that maternal presence constitutes an important part of the early experience. Maternal separation causes a sustained increase in stress responsiveness later in life, along with facilitated anxiety-like behaviors. On the contrary, providing a complex and enriching sensory environment during or after stress, on the other hand, creates resilience to stress. In this chapter, we summarize these environmental influences on the maternal interactions and subsequent stress susceptibility or resilience of the offspring.

Author Correction: Early­life short­term environmental enrichment counteracts the effects of stress on anxiety­like behavior, brain­derived neurotrophic factor and nuclear translocation of glucocorticoid receptors in the basolateral amygdala.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Early-life short-term environmental enrichment counteracts the effects of stress on anxiety-like behavior, brain-derived neurotrophic factor and nuclear translocation of glucocorticoid receptors in the basolateral amygdala.

Early life is a decisive stage for the development of physiological and psychological characteristics of an individual. Any stress or disruption of healthy development at this stage has serious long-lasting consequences for the remaining life. Unfortunately, early life stress is a common occurrence in humans and other animals. In this context, we investigated if the provision of environmental enrichment during the pre-weaning phase of rat pups and dams could alter the consequences of early-life maternal-separation stress. Pre-weaning enrichment rescued the effects of maternal separation on the excess secretion of adrenal stress hormones and anxiety-like behavior during adulthood. Enrichment also reduced the effect of stress on the spine density of basolateral amygdala neurons, a brain region critical for stress-induced facilitation of emotional behaviors. Pre-weaning enrichment, provided during early-life, blunted the effects of maternal separation stress on decreased intra-nuclear translocation of glucocorticoid receptors within the amygdala neurons when tested later in adulthood. Early-life, pre-weaning environmental enrichment also increased the amount of brain-derived neurotrophic factor within adult basolateral amygdala. Our observations showed that environmental manipulation during early formative years could be utilized to build lifelong resilience to stress. Complex naturalistic housing and sensory enrichment is, thus, an useful buffer against an impoverished and stressful childhood.

Female rats are resilient to the behavioral effects of maternal separation stress and exhibit stress-induced neurogenesis.

Early-life stress causes anxiogenesis and sensitivity of stress endocrine axis, facilitated by changes in the basolateral amygdala and hippocampal neurogenesis. In this report, we examined if male-like relationship between early-life stress and anxiety was recapitulated in female rats, along with related neurobiological substrates of the amygdala and the hippocampus. Maternal separation, a paradigm consistently utilized in male rats in most previously published scripts, did not cause similar behavioral consequences in females. Maternal separation caused an increase in adult hippocampal neurogenesis in females without causing substantial differences in dendritic arbors of the basolateral amygdala. Thus, female rats displayed remarkable resilience in the emotional consequences of early-life stress.

Effects of enrichment predominate over those of chronic stress on fear-related behavior in male rats.

The ability to discriminate between spatial contexts is crucial for survival. This ability can be succinctly tested in the paradigm of fear renewal. In this paradigm, a change of spatial context results in robust renewal of conditioned fear, even if the conditioned fear has been previously extinguished. Chronic stress and environmental enrichment are known to affect learning and memory in opposite directions, with the former generally being deleterious. In this study, we examined the effects of chronic stress and enrichment on fear renewal in rats. Fear was evaluated as freezing responses to an auditory conditioning stimulus initially associated with footshocks in context A; fear extinction was evaluated in a novel spatial context (B) without the conditioned stimulus, and renewal in a third context (C) with the auditory cue. Specifically, we aimed to test if environmental enrichment can oppose the effects of chronic stress on fear renewal. We exposed different groups of adult male Wistar rats (6-12 per group) to 10 days of chronic stress (immobilization for 2 h daily), 14 days of enrichment, or a combination of both. We report that chronic stress compromised fear extinction and renewal. In contrast, enrichment re-established fear renewal in chronically stressed rats. Enhanced contextual modulation of fear memories in animals experiencing environmental enrichment while stressed could reflect an adaptive response. This could allow greater flexibility to optimize vigilance in differing spatial contexts.

Neuronal Plasticity in the Amygdala Following Predator Stress Exposure.

Predation causes robust long-term stress-related effects on prey individuals even if they do not get consumed by the predator. Here I review the role of basolateral amygdala (BLA) neurons in the mediation of non-consumptive effects of predation. This brain region is critical for the generation and maintenance of fear response across many phylogenetic groups. The exposure to cues of predator presence activates neurons within the BLA. Hormones secreted during stressful episodes cause long-lasting structural changes in BLA neurons, causing facilitation of endocrine response during subsequent exposure to stressful episodes like later predator exposure. Some studies also suggest that BLA is involved in creating anticipatory defensive behavior in response to the expectation of change in the environment.

Enriched Environment Facilitates Anxiolytic Efficacy Driven by Deep-Brain Stimulation of Medial Prefrontal Cortex.

Deep brain stimulation (DBS) is a widely used treatment for neurodegenerative disorders like Parkinson's disease. Recently, several studies have used preclinical animal models to suggest that DBS has a potential to improve emotional symptoms in mental disorders such as treatment-resistant depression and post-traumatic stress disorder. An important difference between neurodegenerative and emotional disorders is the crucial role of environment in the ontogeny of the latter. Thus, it is important to understand the effects of DBS in the context of environmental variation. In this study, we show that DBS of ventromedial prefrontal cortex reduces anxiety in rats when it is coupled with simultaneous exposure to an enriched environment (EE). In contrast, effects of DBS on anxiety-like behaviors remained equivocal when animals were housed in standard laboratory conditions. These results suggest that the ability of DBS to treat anxiety and related phenotypes can be significantly enhanced by EE opportunities.

Housing environment influences stress-related hippocampal substrates and depression-like behavior.

Rats are widely used animal models for biological psychiatry and neuroscience. Laboratory rats are typically housed in impoverished sensory environments. The lack of species-typical sensory environment might radically change the response of individual animals to stressful and/or threatening episodes. In this report, we demonstrate that behavioral and neural sequelae of chronic stress were modified by sensory environment of adult male rats. This includes effects of stress on the density of spines on CA3 hippocampal neurons, hippocampal neurogenesis and abundance of glucocorticoid or mineralocorticoid receptors. Enrichment also reduced depression-like behavior in a forced swim task. Stress and sensory enrichment evoked opposing effects on all the above endpoints. The sensory enrichment used in this report is of a relatively short duration provided during adulthood. This period excludes critical windows of greater plasticity during pre- and peripubertal stages. Our results suggest that standard housing practices for laboratory rats remain austere concerning sensory requirements of this species. Thus, even a moderate sensory enrichment is capable of reducing high stress-sensitivity and depressive-like behavior in standard laboratory rats.

Complex housing causes a robust increase in dendritic complexity and spine density of medial prefrontal cortical neurons.

Prelimbic cortex and infralimbic cortex, parts of the ventromedial prefrontal cortex, are critical brain regions for generating a flexible behavioral response to changing environmental contingencies. This includes the role of these brain structures in the extinction of learned fear, decision making and retrieval of remote memories. Dendritic structure of medial prefrontal cortex neurons retains significant structural plasticity in adulthood. This has been mainly demonstrated as dendritic atrophy and loss of dendritic spines due to chronic stress. It remains unknown if housing condition of the animals itself can cause opposing changes in the dendritic organization. In that backdrop, here we report that short-term increase in complexity of the housing causes a robust increase in complexity of dendritic architecture of prelimbic and infralimbic neurons. This is reflected in the dendritic expansion of prelimbic neurons and increase in spine density of prelimbic and infralimbic neurons. These results suggest that non-invasive changes in the housing environment can be harnessed to study brain reserves for the flexible and species-typical behaviors.

Dendritic Architecture of Principal Basolateral Amygdala Neurons Changes Congruently with Endocrine Response to Stress.

Animals cope with changing environments through changes in behavior. Such plasticity is, however, marked by substantial inter-individual variability. Neuroendocrine reactivity to challenging environments can be an important predictor of resilience. Both basolateral amygdala (BLA) neurons and adrenal glucocorticoid signaling are integral parts of the stress neuroendocrine response. In this report, we test if individual variation in hormonal response to stress is associated with individual variation in the dendritic complexity of BLA neurons. We report a positive correlation between inter-individual variability in glucocorticoid response and neuronal plasticity in the BLA subsequent to a stressor. This suggests that stressful experiences in the past act as significant sculptors of BLA neuronal plasticity and congruent neuroendocrine response.

Effects of stress or infection on rat behavior show robust reversals due to environmental disturbance.

Background: The behavior of animals is intricately linked to the environment; a relationship that is often studied in laboratory conditions by using environmental perturbations to study biological mechanisms underlying the behavioral change.  Methods: This study pertains to two such well-studied and well-replicated perturbations, i.e., stress-induced anxiogenesis and Toxoplasmagondii -induced loss of innate fear. Here, we demonstrate that behavioral outcomes of these experimental manipulations are contingent upon the ambient quality of the wider environment where animal facilities are situated. Results: During late 2014 and early 2015, a building construction project started adjacent to our animal facility. During this phase, we observed that maternal separation stress caused anxiolysis, rather than historically observed anxiogenesis, in laboratory rats. We also found that Toxoplasma gondii infection caused an increase, rather than historically observed decrease, in innate aversion to predator odors in rats. Conclusion: These observations suggest that effects of stress and Toxoplasma gondii are dependent on variables in the environment that often go unreported in the published literature.

Social stress-related behavior affects hippocampal cell proliferation in mice.

Although social stress inhibits neurogenesis in the adult hippocampus, the extent to which individual differences in stress-related behavior affect hippocampal cell proliferation is not well understood. Based on results from resident-intruder stress tests administered to adult male mice, here we report that individual differences in hippocampal cell proliferation are related to the frequency of defensive behavior, and not the amount of aggression received or the frequency of fleeing. In contrast, access to voluntary wheel-running exercise did not affect hippocampal cell proliferation in either stressed or non-stressed mice. Social stress-induced inhibition of cell proliferation was restricted to the hippocampus, as neither stress nor access to wheel-running exercise altered cell proliferation in the amygdala. These findings indicate that individual differences in stress-related behavior influence cell proliferation in the mouse hippocampus, and may have important implications for understanding structural and functional hippocampal impairments in human psychiatric patients.

Short-term environmental enrichment is sufficient to counter stress-induced anxiety and associated structural and molecular plasticity in basolateral amygdala.

Moderate levels of anxiety enable individual animals to cope with stressors through avoidance, and could be an adaptive trait. However, repeated stress exacerbates anxiety to pathologically high levels. Dendritic remodeling in the basolateral amygdala is proposed to mediate potentiation of anxiety after stress. Similarly, modulation of brain-derived neurotrophic factor is thought to be important for the behavioral effects of stress. In the present study, we investigate if relatively short periods of environmental enrichment in adulthood can confer resilience against stress-induced anxiety and concomitant changes in neuronal arborisation and brain derived neurotrophic factor within basolateral amygdala. Two weeks of environmental enrichment countermanded the propensity of increased anxiety following chronic immobilization stress. Environmental enrichment concurrently reduced dendritic branching and spine density of projection neurons of the basolateral amygdala. Moreover, stress increased abundance of BDNF mRNA in the basolateral amygdala in agreement with the dendritic hypertrophy post-stress and role of BDNF in promoting dendritic arborisation. In contrast, environmental enrichment prevented stress-induced rise in the BDNF mRNA abundance. Gain in body weights and adrenal weights remained unaffected by exposure to environmental enrichment. These observations suggest that a short period of environmental enrichment can provide resilience against maladaptive effects of stress on hormonal, neuronal and molecular mediators of anxiogenesis.

Chronic stress induces contrasting patterns of dendritic remodeling in hippocampal and amygdaloid neurons.

The hippocampus and the amygdala are essential components of the neural circuitry mediating stress responses. The hippocampus, which provides negative feedback regulation of the stress response, is particularly vulnerable to degenerative changes caused by chronic stress. Unlike the hippocampus, relatively little is known about how stress affects the amygdala and the nature of its role in the stress response. Hence, we examined the effects of two different models of chronic stress on hippocampal and amygdaloid neuronal morphology in rats. In agreement with previous reports, chronic immobilization stress (CIS) induced dendritic atrophy and debranching in CA3 pyramidal neurons of the hippocampus. In striking contrast, pyramidal and stellate neurons in the basolateral complex of the amygdala exhibited enhanced dendritic arborization in response to the same CIS. Chronic unpredictable stress (CUS), however, had little effect on CA3 pyramidal neurons and induced atrophy only in BLA bipolar neurons. These results indicate that chronic stress can cause contrasting patterns of dendritic remodeling in neurons of the amygdala and hippocampus. Moreover, CIS, but not CUS, reduced open-arm activity in the elevated plus-maze. These findings raise the possibility that certain forms of chronic stress, by affecting specific neuronal elements in the amygdala, may lead to behavioral manifestations of enhanced emotionality. Thus, stress-induced structural plasticity in amygdala neurons may provide a candidate cellular substrate for affective disorders triggered by chronic stress.

Chronic-stress induced modulation of different states of anxiety-like behavior in female rats.

Stress facilitates emotionality and consolidation of aversive memories in male rodents. In addition, considerable sexual dimorphism has been observed in animal and clinical literature, both in response to stress and predisposition to anxiety disorders thought to be exacerbated by stress. In view of this, we investigated effects of chronic immobilization stress and chronic unpredictable stress on anxiety-like behavior exhibited by female Wistar rats, using the elevated plus-maze. Neither of the stress paradigms employed in this study significantly influenced anxiety, as manifested by similar open-arm exploration in control and treated animals. Previous studies have reported that in males, exposure to elevated plus-maze during an initial trial significantly reduces open-arm exploration in subsequent retesting, an effect attributed to consolidation of aversive experience of the initial exposure. Control female animals, during a second exposure to the maze 72 h after the first trial, displayed a similar shift to a state of enhanced anxiety. Furthermore, exposure to stress did not affect such consolidation of anxiety, as evidenced by similar reduction in open-arm exploration between control and stressed animals during retesting. We conclude that female rats are insensitive to chronic stress in terms of facilitation and consolidation of anxiety.