The Influence of the Estrous Cycle on Neuropeptide S Receptor-Mediated Behaviors.

The Neuropeptide S receptor (NPSR) has been identified as a potential therapeutic target for anxiety and post-traumatic stress disorder. Central administration of Neuropeptide S (NPS) in male mice produces anxiolytic-like effects, hyperlocomotion, and memory enhancement. Currently, the literature is limited in the number of studies investigating the effects of NPS in female test subjects despite females facing a higher prevalence of anxiety-related pathology, as well as greater risk for adverse effects while taking psychoactive drugs. Moreover, no previous studies have considered the influence of estrous cycle on the effects of NPS. The current study investigates whether NPS-mediated behavioral phenotypes seen in males translate to females, and whether they are affected by estrous cycle stage. Female C57BL/6NCr mice were intracerebroventricularly (ICV) cannulated and underwent behavioral paradigms to test locomotion, anxiety, and memory. Estrous cycle stage was determined through examination of vaginal cytology. Our results provide evidence that NPS-mediated behaviors are influenced by the estrous cycle. Administration of NPS decreased anxiety-like behaviors more robustly when the female mice were in high estrogen stages of the estrous cycle. Therefore, the desired anxiolytic-like effects of targeting the NPSR are intact in female mice. However, these effects may to be influenced by the stage of the estrous cycle. The NPSR remains a strong potential drug target for new anxiolytic compounds and based on our initial observations further studies exploring the interaction of estrous cycle and the NPS-system are warranted. Significance Statement The neuropeptide S (NPS) receptor has been identified as a potential target for treating anxiety, a condition that is most prevalent in females. Therefore, the potential interaction of estrous cycle with the NPS-system described in the current study is an important first step in understanding the function of the NPS-system in females.

Site-Specific knockdown of microglia in the locus coeruleus regulates hypervigilant responses to social stress in female rats.

BACKGROUND: Women are at increased risk for psychosocial stress-related anxiety disorders, yet mechanisms regulating this risk are unknown. Psychosocial stressors activate microglia, and the resulting neuroimmune responses that females exhibit heightened sensitivity to may serve as an etiological factor in their elevated risk. However, studies examining the role of microglia during stress in females are lacking. METHODS: Microglia were manipulated in the stress-sensitive locus coeruleus (LC) of female rats in the context of social stress in two ways. First, intra-LC lipopolysaccharide (LPS; 0 or 3 µg/side, n = 5-6/group), a potent TLR4 agonist and microglial activator, was administered. One hour later, rats were exposed to control or an aggressive social defeat encounter between two males (WS, 15-min). In a separate study, females were treated with intra-LC or intra-central amygdala mannosylated liposomes containing clodronate (m-CLD; 0 or 25 µg/side, n = 13-14/group), a compound toxic to microglia. WS-evoked burying, cardiovascular responses, and sucrose preference were measured. Brain and plasma cytokines were quantified, and cardiovascular telemetry assessed autonomic balance. RESULTS: Intra-LC LPS augmented the WS-induced burying response and increased plasma corticosterone and interleukin-1ß (IL-1ß). Further, the efficacy and selectivity of microinjected m-CLD was fully characterized. In the context of WS, intra-LC m-CLD attenuated the hypervigilant burying response during WS as well as the accumulation of intra-LC IL-1ß. Intra-central amygdala m-CLD had no effect on WS-evoked behavior. CONCLUSIONS: These studies highlight an innovative method for depleting microglia in a brain region specific manner and indicate that microglia in the LC differentially regulate hypervigilant WS-evoked behavioral and autonomic responses.

Aging triggers an upregulation of a multitude of cytokines in the male and especially the female rodent hippocampus but more discrete changes in other brain regions.

BACKGROUND: Despite widespread acceptance that neuroinflammation contributes to age-related cognitive decline, studies comparing protein expression of cytokines in the young versus old brains are surprisingly limited in terms of the number of cytokines and brain regions studied. Complicating matters, discrepancies abound-particularly for interleukin 6 (IL-6)-possibly due to differences in sex, species/strain, and/or the brain regions studied. METHODS: As such, we clarified how cytokine expression changes with age by using a Bioplex and Western blot to measure multiple cytokines across several brain regions of both sexes, using 2 mouse strains bred in-house as well as rats obtained from NIA. Parametric and nonparametric statistical tests were used as appropriate. RESULTS: In the ventral hippocampus of C57BL/6J mice, we found age-related increases in IL-1α, IL-1ß, IL-2, IL-3, IL-4, IL-6, IL-9, IL-10, IL-12p40, IL-12p70, IL-13, IL-17, eotaxin, G-CSF, interfeuron δ, KC, MIP-1a, MIP-1b, rantes, and TNFα that are generally more pronounced in females, but no age-related change in IL-5, MCP-1, or GM-CSF. We also find aging is uniquely associated with the emergence of a module (a.k.a. network) of 11 strongly intercorrelated cytokines, as well as an age-related shift from glycosylated to unglycosylated isoforms of IL-10 and IL-1ß in the ventral hippocampus. Interestingly, age-related increases in extra-hippocampal cytokine expression are more discreet, with the prefrontal cortex, striatum, and cerebellum of male and female C57BL/6J mice demonstrating robust age-related increase in IL-6 expression but not IL-1ß. Importantly, we found this widespread age-related increase in IL-6 also occurs in BALB/cJ mice and Brown Norway rats, demonstrating conservation across species and rearing environments. CONCLUSIONS: Thus, age-related increases in cytokines are more pronounced in the hippocampus compared to other brain regions and can be more pronounced in females versus males depending on the brain region, genetic background, and cytokine examined.

Sex Differences in the Inflammatory Consequences of Stress: Implications for Pharmacotherapy.

Women are at significantly greater risk of developing stress-related disorders such as depression. The increased risk begins during puberty and continues throughout life until menopause, suggesting a role for ovarian hormones in this increased susceptibility. Importantly, inflammation has been gaining momentum in its role in the pathogenesis of depression. Herein, clinical and preclinical studies have been reviewed to better understand how sex differences within the immune system may contribute to exaggerated risk of depression in females. First, studies that investigate the ability of psychologic stress episodes to engage the inflammatory systems both in the brain and periphery are reviewed with a special focus on sex-specific effects. Moreover, studies are discussed that identify whether imbalanced inflammatory milieu contributes to the development of depression in males versus females and whether these effects are regulated by estradiol. Importantly, we propose a locus coeruleus-norepinephrine-cytokine circuit as a conduit through which stress could increase stress susceptibly in females. Finally, the anti-inflammatory capacity of traditional and nontraditional antidepressants is investigated, with the goal of providing a better understanding of pharmacotherapeutics to enhance strategies to personalize antidepressant treatments between the sexes. The studies reviewed herein strongly support the need for further studies to elucidate whether females are especially sensitive to anti-inflammatory compounds as adjuvants to traditional therapies. SIGNIFICANCE STATEMENT: Women have hve an increased risk of developing stress-related disorders such as depression. In this review, literature from clinical and preclinical studies are integrated to define sex differences in stress-induced inflammatory responses as a potential source for the etiology of sex differences in depressive disorders. Moreover, the anti-inflammatory capacity of traditional and nontraditional antidepressants is reviewed to inform on potential pharmacotherapeutic strategies to personalize antidepressant therapy in a sex-dependent manner.

The contribution of the locus coeruleus-norepinephrine system in the emergence of defeat-induced inflammatory priming.

Exposure to psychosocial stress is known to precipitate the emergence of stress related psychiatric disorders such as depression and anxiety. While mechanisms by which this occurs remain largely unclear, recent evidence points towards a causative role for inflammation. Neurotransmitters, such as norepinephrine (NE), are capable of regulating expression of proinflammatory cytokines and thus may contribute to the emergence of stress-related disorders. The locus coeruleus (LC) is the major source of norepinephrine (NE) to the brain and therefore the current study utilized N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4), an LC selective noradrenergic neurotoxin, to determine the discrete involvement of the LC-NE system in social defeat-induced inflammation in LC projection regions including the central amygdala (CeA), dorsal raphe (DR) and plasma. In the current study, rats were exposed to brief social defeat or control manipulations on 5 consecutive days. To determine whether a history of social defeat enhanced or "primed" the inflammatory response to a subsequent defeat exposure, all rats regardless of stress history were exposed to an acute social defeat challenge immediately preceeding tissue collection. As anticipated, prior history of social defeat primed inflammatory responses in the plasma and CeA while neuroinflammation in the DR was markedly reduced. Notably, DSP-4 treatment suppressed stress-induced circulating inflammatory cytokines independent of prior stress history. In contrast, neuroinflammation in the CeA and DR were greatly augmented selectively in DSP-4 treated rats with a history of social defeat. Together these data highlight the dichotomous nature of NE in stress-induced inflammatory priming in the periphery and the brain and directly implicate the LC-NE system in these processes.

Common pathways and communication between the brain and heart: connecting post-traumatic stress disorder and heart failure.

Psychiatric illnesses and cardiovascular disease (CVD) contribute to significant overall morbidity, mortality, and health care costs, and are predicted to reach epidemic proportions with the aging population. Within the Veterans Administration (VA) health care system, psychiatric illnesses such as post-traumatic stress disorder (PTSD) and CVD such as heart failure (HF), are leading causes of hospital admissions, prolonged hospital stays, and resource utilization. Numerous studies have demonstrated associations between PTSD symptoms and CVD endpoints, particularly in the Veteran population. Not only does PTSD increase the risk of HF, but this relationship is bi-directional. Accordingly, a VA-sponsored conference entitled "Cardiovascular Comorbidities in PTSD: The Brain-Heart Consortium" was convened to explore potential relationships and common biological pathways between PTSD and HF. The conference was framed around the hypothesis that specific common systems are dysregulated in both PTSD and HF, resulting in a synergistic acceleration and amplification of both disease processes. The conference was not intended to identify all independent pathways that give rise to PTSD and HF, but rather identify shared systems, pathways, and biological mediators that would be modifiable in both disease processes. The results from this conference identified specific endocrine, autonomic, immune, structural, genetic, and physiological changes that may contribute to shared PTSD-CVD pathophysiology and could represent unique opportunities to develop therapies for both PTSD and HF. Some recommendations from the group for future research opportunities are provided.

Statistical considerations in reporting cardiovascular research.

The problem of inadequate statistical reporting is long standing and widespread in the biomedical literature, including in cardiovascular physiology. Although guidelines for reporting statistics have been available in clinical medicine for some time, there are currently no guidelines specific to cardiovascular physiology. To assess the need for guidelines, we determined the type and frequency of statistical tests and procedures currently used in the American Journal of Physiology-Heart and Circulatory Physiology. A PubMed search for articles published in the American Journal of Physiology-Heart and Circulatory Physiology between January 1, 2017, and October 6, 2017, provided a final sample of 146 articles evaluated for methods used and 38 articles for indepth analysis. The t-test and ANOVA accounted for 71% (212 of 300 articles) of the statistical tests performed. Of six categories of post hoc tests, Bonferroni and Tukey tests were used in 63% (62 of 98 articles). There was an overall lack in details provided by authors publishing in the American Journal of Physiology-Heart and Circulatory Physiology, and we compiled a list of recommended minimum reporting guidelines to aid authors in preparing manuscripts. Following these guidelines could substantially improve the quality of statistical reports and enhance data rigor and reproducibility.

The protective effects of resveratrol on social stress-induced cytokine release and depressive-like behavior.

Social stress is a risk factor for psychiatric disorders, however only a subset of the population is susceptible while others remain resilient. Inflammation has been linked to the pathogenesis of psychosocial disorders in humans and may underlie these individual differences. Using a resident-intruder paradigm capable of revealing individual differences in coping behavior and inflammatory responses, the present study determined if resveratrol (RSV; 0, 10, 30mg/kg/day) protected against persistent stress-induced inflammation in socially defeated rats. Furthermore, the antidepressant efficacy of RSV was evaluated using the sucrose preference test. Active coping rats were characterized by more time spent in upright postures and increased defeat latencies versus passive coping rats. Five days after defeat, flow cytometry revealed enhanced stimulation of proinflammatory proteins (IL-ß, TNF-α) in spleen cells of passive rats as compared to active coping and controls, an effect that was blocked by both doses of RSV. Furthermore, only passive coping rats exhibited increased proinflammatory proteins (IL-1ß, TNF-α, GM-CSF) in the locus coeruleus (LC), a noradrenergic brain region implicated in depression. Notably, only 30mg/kg RSV blocked LC neuroinflammation and importantly, was the only dose that blocked anhedonia. Alternatively, while stress had minimal impact on resting cytokines in the dorsal raphe (DR), RSV dose-dependently reduced DR cytokine expression. However, this did not result in changes in indoleamine 2,3-dioxygenase activity or serotonin levels. Taken together, these data suggest that social stress-induced depressive-like behavior evident in passive coping rats may be driven by stress-induced neuroinflammation and highlight natural anti-inflammatory agents to protect against social stress-related consequences.

Individual differences in the neurobiology of social stress: implications for depression-cardiovascular disease comorbidity.

Stress initiates a cascade of complex neural and peripheral changes that promote healthy adaption to stress, but when unabated, leads to pathology. Fascinating individual differences arise in the ability to cope with a stressor, rendering an individual more or less likely to develop stress-induced pathologies such as depression, anxiety, and cardiovascular disease. In this review we evaluate recent findings that investigate the neural underpinnings of adopting a passive or active coping response during social defeat stress. Because passive coping is associated with vulnerability to stress-related pathologies and active coping confers resiliency, understanding neurobiological adaptations associated with these diverse coping strategies may reveal biomarkers or targets impacting stress susceptibility. The co-occurrence of stress-induced depression and cardiovascular disease is becoming increasingly clear. Therefore this review focuses on the central mechanisms capable of contributing to psychopathology and cardiovascular disease such as corticotropin releasing factor, neuropeptide Y, monoamines, cytokines and oxidative stress. The impetus for this review is to highlight neurobiological systems that warrant further evaluation for their contribution to the pathophysiology of depression-cardiovascular disease comorbidity.

Voluntary wheel running as a promising strategy to promote autonomic resilience to social stress in females: Vagal tone lies at the heart of the matter.

Social stress is a major risk factor for comorbid conditions including cardiovascular disease and depression. While women exhibit 2-3× the risk for these stress-related disorders compared to men, the mechanisms underlying heightened stress susceptibility among females remain largely unknown. Due to a lack in understanding of the pathophysiology underlying stress-induced comorbidities among women, there has been a significant challenge in developing effective therapeutics. Recently, a causal role for inflammation has been established in the onset and progression of comorbid cardiovascular disease/depression, with women exhibiting increased sensitivity to stress-induced immune signaling. Importantly, reduced vagal tone is also implicated in stress susceptibility, through a reduction in the vagus nerve's well-recognized anti-inflammatory properties. Thus, examining therapeutic strategies that stabilize vagal tone during stress may shed light on novel targets for promoting stress resilience among women. Recently, accumulating evidence has demonstrated that physical activity exerts cardio- and neuro-protective effects by enhancing vagal tone. Based on this evidence, this mini review provides an overview of comorbid cardiovascular and behavioral dysfunction in females, the role of inflammation in these disorders, how stress may impart its negative effects on the vagus nerve, and how exercise may act as a preventative. Further, we highlight a critical gap in the literature with regard to the study of females in this field. This review also presents novel data that are the first to demonstrate a protective role for voluntary wheel running over vagal tone and biomarkers of cardiac dysfunction in the face of social stress exposure in female rats.

The functional role of locus coeruleus microglia in the female stress response.

Neuropsychiatric disorders that result from stress exposure are highly associated with central inflammation. Our previous work established that females selectively exhibit heightened proinflammatory cytokine production within the noradrenergic locus coeruleus (LC) along with a hypervigilant behavioral phenotype in response to witnessing social stress, and ablation of microglia using pharmacological techniques prevents this behavioral response. These studies were designed to further investigate the impact of stress-induced neuroimmune signaling on the long-term behavioral and neuronal consequences of social stress exposure in females using chemogenetics. We first characterized the use of an AAV-CD68-Gi-DREADD virus targeted to microglia within the LC and confirmed viral transduction, selectivity, and efficacy. Clozapine-n-oxide (CNO) was used for the suppression of microglial reactivity during acute and chronic exposure to vicarious/witness social defeat in female rats. Chemogenetic-mediated inhibition of microglial reactivity during stress blunted the neuroimmune response to stress and prevented both acute and long-term hypervigilant behavioral responses. Further, a history of microglial suppression during stress prevented the heightened LC activity typically observed in response to stress cues. These studies are among the first to use a chemogenetic approach to inhibit microglia within the female brain in vivo and establish LC inflammation as a key mechanism underlying the behavioral and neuronal responses to social stress in females.

A corticotropin-releasing factor receptor antagonist improves urodynamic dysfunction produced by social stress or partial bladder outlet obstruction in male rats.

Barrington's nucleus, in the pons, regulates micturition through spinal projections to preganglionic parasympathetic neurons. The stress neuropeptide CRF is prominent in these projections and has an inhibitory influence. Social stress in rats causes urinary retention and abnormal urodynamics resembling those produced by partial bladder outlet obstruction (pBOO), and this is associated with CRF upregulation in Barrington's nucleus. Here, we examined the role of CRF in social stress- and pBOO-induced urodynamic dysfunction by assessing the ability of a CRF1 receptor antagonist to alter these effects. Male rats exposed to repeated resident-intruder stress were administered vehicle or a CRF1 antagonist (NBI-30775) daily prior to the stress. Urodynamic function was recorded in the unanesthetized state 72 h after the final stress. NBI-30775 prevented the increased intermicturition interval, micturition volume, and bladder capacity produced by social stress, but not the increase in CRF expression in Barrington's nucleus neurons. The urinary dysfunction was also partly prevented by shRNA targeting of CRF in Barrington's nucleus, suggesting that stress-induced urinary dysfunction results, in part, from CRF upregulation in Barrington's nucleus and enhanced postsynaptic effects in the spinal cord. Finally, NBI-30775 improved urodynamic function of rats that had pBOO of 2-wk duration when administered daily during the second week but did not block the increase in CRF expression in Barrington's nucleus neurons. These findings implicate a role for Barrington's nucleus CRF in stress- and pBOO-induced urodynamic changes and suggest that CRF1 antagonists may be useful therapeutic agents for the treatment of urinary dysfunction.

Estrogen receptor beta in the central amygdala regulates the deleterious behavioral and neuronal consequences of repeated social stress in female rats.

While over 95% of the population has reported experiencing extreme stress or trauma, females of reproductive age develop stress-induced neuropsychiatric disorders at twice the rate of males. This suggests that ovarian hormones may facilitate neural processes that increase stress susceptibility and underlie the heightened rates of these disorders, like depression and anxiety, that result from stress exposure in females. However, there is contradicting evidence in the literature regarding estrogen's role in stress-related behavioral outcomes. Estrogen signaling through estrogen receptor beta (ERß) has been traditionally thought of as anxiolytic, but recent studies suggest estrogen exhibits distinct effects in the context of stress. Furthermore, ERß is found abundantly in many stress-sensitive brain loci, including the central amygdala (CeA), in which transcription of the vital stress hormone, corticotropin releasing factor (CRF), can be regulated by an estrogen response element. Therefore, these experiments sought to identify the role of CeA ERß activity during stress on behavioral outcomes in naturally cycling, adult, female Sprague-Dawley rats. Rats were exposed to an ethological model of vicarious social stress, witness stress (WS), in which they experienced the sensory and psychological aspects of an aggressive social defeat encounter between two males. Following WS, rats exhibited stress-induced anxiety-like behaviors in the marble burying taskand brain analysis revealed increased ERß and CRF specifically within the CeA following exposure to stress cues. Subsequent experiments were designed to target this receptor in the CeA using microinjections of the ERß antagonist, PHTPP, prior to each stress session. During WS, estrogen signaling through ERß was responsible for the behavioral sensitization to repeated social stress. Sucrose preference, acoustic startle, and marble burying tasks determined that blocking ERß in the CeA during WS prevented the development of depressive-, anxiety-like, and hypervigilant behaviors. Additionally, brain analysis revealed a long-term decrease of intra-CeA CRF expression in PHTPP-treated rats. These experiments indicate that ERß signaling in the CeA, likely through its effects on CRF, contributes to the development of negative valence behaviors that result from exposure to repeated social stress in female rats.

Stress- and drug-induced neuroimmune signaling as a therapeutic target for comorbid anxiety and substance use disorders.

Stress and substance use disorders remain two of the most highly prevalent psychiatric conditions and are often comorbid. While individually these conditions have a debilitating impact on the patient and a high cost to society, the symptomology and treatment outcomes are further exacerbated when they occur together. As such, there are few effective treatment options for these patients, and recent investigation has sought to determine the neural processes underlying the co-occurrence of these disorders to identify novel treatment targets. One such mechanism that has been linked to stress- and addiction-related conditions is neuroimmune signaling. Increases in inflammatory factors across the brain have been heavily implicated in the etiology of these disorders, and this review seeks to determine the nature of this relationship. According to the "dual-hit" hypothesis, also referred to as neuroimmune priming, prior exposure to either stress or drugs of abuse can sensitize the neuroimmune system to be hyperresponsive when exposed to these insults in the future. This review completes an examination of the literature surrounding stress-induced increases in inflammation across clinical and preclinical studies along with a summarization of the evidence regarding drug-induced alterations in inflammatory factors. These changes in neuroimmune profiles are also discussed within the context of their impact on the neural circuitry responsible for stress responsiveness and addictive behaviors. Further, this review explores the connection between neuroimmune signaling and susceptibility to these conditions and highlights the anti-inflammatory pharmacotherapies that may be used for the treatment of stress and substance use disorders.

Neuroinflammation and Mitochondrial Dysfunction Link Social Stress to Depression.

Major depressive disorder is a debilitating mental illness and a leading cause of global disease burden. While many etiological factors have been identified, social stress is a highly prevalent causative factor for the onset of depression. Unfortunately, rates of depression continue to increase around the world, and the recent COVID-19 pandemic has further exacerbated this mental health crisis. Though several therapeutic strategies are available, nearly 50% of patients who receive treatment never reach remission. The exact mechanisms by which social stress exposure promotes the development of depression are unclear, making it challenging to develop novel and more effective therapeutics. However, accumulating evidence points to a role for stress-induced neuroinflammation, particularly in treatment-resistant patients. Moreover, recent evidence has expanded the concept of the pathogenesis of depression to mitochondrial dysfunction, suggesting that the combined effects of social stress on mitochondria and inflammation may synergize to facilitate stress-related depression. In this chapter, we review evidence for neuroinflammation and mitochondrial dysfunction in the pathogenesis of social stress-induced depression and discuss these in the context of novel therapeutic targets for the treatment of depression.

Both CRF1 and CRF2 receptors in the bed nucleus of stria terminalis are involved in baroreflex impairment evoked by chronic stress in rats.

Chronic exposure to adverse events has been proposed as a prominent factor involved in etiology and progression of cardiovascular dysfunctions in humans and animals. However, the neurobiological mechanisms involved are still poorly understood. In this sense, chronic stress has been reported to evoke neuroplasticity in corticotropin-releasing factor (CRF) neurotransmission in several limbic structures, including the bed nucleus of the stria terminalis. However, a possible involvement of BNST CRF neurotransmission in cardiovascular dysfunctions evoked by chronic stress has never been reported. Thus, this study investigated the involvement of CRF1 and CRF2 receptors within the BNST in cardiovascular changes evoked by chronic stress in rats. We identified that exposure to a 10-day chronic variable stress (CVS) protocol decreased expression of both CRF1 and CRF2 receptors within the BNST. These effects were followed by increased arterial pressure and impairment of baroreflex function, but without changes on heart rate. Bilateral microinjection of either the selective CRF1 receptor antagonist CP376395 or the selective CRF2 receptor antagonist antisauvagine-30 into the BNST did not affect CVS-evoked arterial pressure increase. Nevertheless, BNST treatment with CP376395 decreased both tachycardic and bradycardic responses of the baroreflex in non-stressed rats; but these effects were not identified in chronically stressed animals. BNST pharmacological treatment with antisauvagine-30 decreased the reflex tachycardia in control animals, whereas reflex bradycardic response was increased in CVS animals. Altogether, the results reported in the present study indicate that down regulation of both CRF1 and CRF2 receptors within the BNST is involved in baroreflex impairment evoked by chronic stress.

Advances in understanding mechanisms and therapeutic targets to treat comorbid depression and cardiovascular disease.

Chronic or repeated social stress exposure often precipitates the onset of depression and cardiovascular disease (CVD). Despite a clear clinical association between CVD and depression, the pathophysiology underlying these comorbid conditions is unclear. Chronic exposure to social stress can lead to immune system dysregulation, mitochondrial dysfunction, and vagal withdrawal. Further, regular physical exercise is well-known to exert cardioprotective effects, and accumulating evidence demonstrates the antidepressant effect of exercise. This review explores the contribution of inflammation, mitochondrial dysfunction, and vagal withdrawal to stress-induced depression and CVD. Evidence for therapeutic benefits of exercise, anti-inflammatory therapies, and vagus nerve stimulation are also reviewed. Benefits of targeted therapeutics of mitochondrial agents, anti-inflammatory therapies, and vagus nerve stimulation are discussed. Importantly, the ability of exercise to impact each of these factors is also reviewed. The current findings described here implicate a new direction for research, targeting the shared mechanisms underlying comorbid depression-CVD. This will guide the development of novel therapeutic strategies for the prevention and treatment of these stress-related pathologies, particularly within treatment-resistant populations.

Putative Inflammatory Sensitive Mechanisms Underlying Risk or Resilience to Social Stress.

It has been well recognized that exposure to stress can lead to the onset of psychosocial disorders such as depression. While there are a number of antidepressant therapies currently available and despite producing immediate neurochemical alterations, they require weeks of continuous use in order to exhibit antidepressant efficacy. Moreover, up to 30% of patients do not respond to typical antidepressants, suggesting that our understanding of the pathophysiology underlying stress-induced depression is still limited. In recent years inflammation has become a major focus in the study of depression as several clinical and preclinical studies have demonstrated that peripheral and central inflammatory mediators, including interleukin (IL)-1ß, are elevated in depressed patients. Moreover, it has been suggested that inflammation and particularly neuroinflammation may be a direct and immediate link in the emergence of stress-induced depression due to the broad neural and glial effects that are elicited by proinflammatory cytokines. Importantly, individual differences in inflammatory reactivity may further explain why certain individuals exhibit differing susceptibility to the consequences of stress. In this review article, we discuss sources of individual differences such as age, sex and coping mechanisms that are likely sources of distinct changes in stress-induced neuroimmune factors and highlight putative sources of exaggerated neuroinflammation in susceptible individuals. Furthermore, we review the current literature of specific neural and glial mechanisms that are regulated by stress and inflammation including mitochondrial function, oxidative stress and mechanisms of glutamate excitotoxicity. Taken together, the impetus for this review is to move towards a better understanding of mechanisms regulated by inflammatory cytokines and chemokines that are capable of contributing to the emergence of depressive-like behaviors in susceptible individuals.

Essential Role of Ovarian Hormones in Susceptibility to the Consequences of Witnessing Social Defeat in Female Rats.

BACKGROUND: Women are at greater risk than men of developing depression and comorbid disorders such as cardiovascular disease. This enhanced risk begins at puberty and ends following menopause, suggesting a role for ovarian hormones in this sensitivity. Here we used a model of psychosocial witness stress in female rats to determine the stress-induced neurobiological adaptations that underlie stress susceptibility in an ovarian hormone-dependent manner. METHODS: Intact or ovariectomized (OVX) female rats were exposed to five daily 15-minute witness-stress exposures. Witness-stress-evoked burying, behavioral despair, and anhedonia were measured. Cardiovascular telemetry was combined with plasma measurements of inflammation, epinephrine, and corticosterone as indices of cardiovascular dysfunction. Finally, levels of interleukin-1ß and corticotropin-releasing factor were assessed in the central amygdala. RESULTS: Witness stress produced anxiety-like burying, depressive-like anhedonia, and behavioral despair selectively in intact female rats, which was associated with enhanced sympathetic responses during stress, including increased blood pressure, heart rate, and arrhythmias. Moreover, intact female rats exhibited increases in 12-hour resting systolic pressure and heart rate and reductions in heart rate variability. Notably, OVX female rats remained resilient. Moreover, intact, but not OVX, female rats exposed to witness stress exhibited a sensitized cytokine and epinephrine response to stress and distinct increases in levels of corticotropin-releasing factor and interleukin-1ß in the central amygdala. CONCLUSIONS: Together these data suggest that ovarian hormones play a critical role in the behavioral, inflammatory, and cardiovascular susceptibility to social stress in female rats and reveal putative systems that are sensitized to stress in an ovarian hormone-dependent manner.