James P Herman

• PhD
• University of Cincinnati

Responses to acute stress function to restore homeostasis. Hence, the study of neurophysiological responses to acute stress helps to understand mechanisms underlying adaptive coping in the face of environmental demands. The infralimbic medial prefrontal cortex (IL-mPFC) modulates the switch between behavioral coping styles, and acute stress enhance...

Post-Traumatic Stress Disorder (PTSD) is a debilitating condition in which a traumatic experience triggers symptoms related to re-experiencing, avoidance, arousal, and mood dysregulation. PTSD negatively impacts 6% of people during their lifetime, with women being disproportionally affected and exhibiting different, more severe symptoms than men. D...

The paraventricular nucleus of the hypothalamus (PVN) regulates physiological and behavioural responses evoked by stressful stimuli, but the local neurochemical and signalling mechanisms involved are not completely understood. The soluble guanylate cyclase (sGC) within the PVN is implicated in autonomic and cardiovascular control in rodents under r...

Chronic stress leads to hypofunction of the medial prefrontal cortex (mPFC), mechanisms of which remain to be determined. Enhanced activation of GABAergic of parvalbumin (PV) expressing interneurons (INs) is thought to play a role in stress-induced prefrontal inhibition. In this study, we tested whether chemogenetic inhibition of mPFC PV INs after...

Psychological loss is a common experience that erodes well-being and negatively impacts quality of life. The molecular underpinnings of loss are poorly understood. Here, we investigate the mechanisms of loss using an environmental enrichment removal (ER) paradigm in male rats. The basolateral amygdala (BLA) was identified as a region of interest, d...

Status epilepticus (SE) is a life-threatening medical emergency with significant morbidity and mortality. SE is associated with a robust and sustained increase in serum glucocorticoids, reaching concentrations sufficient to activate the dense population of glucocorticoid receptors (GRs) expressed among hippocampal excitatory neurons. Glucocorticoid...

Psychological loss is a common experience that erodes well-being and negatively impacts quality of life. The molecular underpinnings of loss are poorly understood, making it challenging to develop treatment strategies. Here, we investigate the mechanisms of loss using an enrichment removal (ER) paradigm in rats. A comprehensive multi-omics investig...

In psychiatric disorders, mismatches between disease states and therapeutic strategies are highly pronounced, largely because of unanswered questions regarding specific vulnerabilities of different cell types and therapeutic responses. Which cellular events (housekeeping or salient) are most affected? Which cell types succumb first to challenges, a...

The hippocampus has become a significant target of stress research in recent years because of its role in cognitive functioning, neuropathology, and regulation of the hypothalamic-pituitary-adrenal (HPA) axis. Despite the pervasive impact of stress on psychiatric and neurological disease, many of the circuit- and cell-dependent mechanisms giving ri...

Background Adolescent brains are sensitive to stressors. However, under certain circumstances, developmental stress can promote an adaptive phenotype, allowing individuals to cope better with adverse situations in adulthood, thereby contributing to resilience. Methods Sprague Dawley rats (50 males, 48 females) were subjected to adolescent chronic...

Glucocorticoid signaling plays major roles in energy homeostasis and adaptation to adversity, and dysregulation of this process is linked to systemic and psychological pathology. Over the last several decades, new work has challenged many of the long-standing assumptions regarding regulation of glucocorticoid secretion and glucocorticoid signaling...

In psychiatric disorders, mismatches between disease-states and therapeutic strategies are highly pronounced, largely because of unanswered questions regarding specific vulnerabilities of different cell-types and therapeutic responses. Which cellular events (housekeeping or salient) are most affected? Which cell-types succumb first to challenges, a...

The common molecular mechanisms underlying psychiatric disorders are not well understood. Prior attempts to assess the pathological mechanisms responsible for psychiatric disorders have been limited by biased selection of comparable disorders, datasets/cohort availability, and challenges with data normalization. Here, using DisGeNET, a gene-disease...

Post-traumatic stress disorder (PTSD) is a chronic, debilitating mental illness marked by abnormal fear responses and deficits in extinction of fear memories. The pathophysiology of PTSD is linked to decreased activation of the ventromedial prefrontal cortex (vmPFC). This study aims to investigate underlying functional changes in synaptic drive and...

Background: Stress during adolescence is usually associated with psychopathology later in life. However, under certain circumstances, developmental stress can promote an adaptive phenotype, allowing individuals to cope better with adverse situations in adulthood, thereby contributing to resilience. Methods: Sprague Dawley rats (50 males, 48 females...

Pituitary adenylate cyclase-activating polypeptide (PACAP) is an excitatory neuromodulatory peptide strongly implicated in nervous stress processing. Human polymorphism of the primary PACAP receptor (PAC1) is linked to psychiatric disorders, including posttraumatic stress disorder (PTSD). Prefrontal cortex PACAP signaling is associated with process...

Post-traumatic stress disorder (PTSD) is a chronic, debilitating mental illness marked by abnormal fear responses and deficits in extinction of fear memories. The pathophysiology of PTSD is linked to decreased activation of the ventromedial prefrontal cortex (vmPFC). This study aims to investigate underlying functional changes in synaptic drive and...

Objective Glucocorticoid levels rise rapidly following status epilepticus and remain elevated for weeks after the injury. To determine whether glucocorticoid receptor activation contributes to the pathological sequelae of status epilepticus, mice were treated with a novel glucocorticoid receptor modulator, C108297. Methods Mice were treated with e...

Regulation of stress reactivity is a fundamental priority of all organisms. Stress responses are critical for survival, yet can also cause physical and psychological damage. This review provides a synopsis of brain mechanisms designed to control physiological responses to stress, focusing primarily on glucocorticoid secretion via the hypothalamo-pi...

Exposure to prolonged stress is a major risk-factor for psychiatric disorders such as generalized anxiety and major depressive disorder. Human imaging studies have identified structural and functional abnormalities in the prefrontal cortex of subjects with depression and anxiety disorders, particularly Brodmann's area 25 (BA25). Further, deep brain...

Hypofunction of the prefrontal cortex (PFC) contributes to stress-related neuropsychiatric illnesses. Mechanisms leading to prefrontal hypoactivity remain to be determined. Prior evidence suggests that chronic stress leads to an increase in activity of parvalbumin (PV) expressing GABAergic interneurons (INs) in the PFC. The purpose of the study was...

The common molecular mechanisms underlying psychiatric disorders are not well understood. Prior attempts to assess the pathological mechanisms responsible for psychiatric disorders have been limited by biased selection of comparable disorders, datasets as well as challenges associated with data normalization. However, publicly available databases o...

Exposure to prolonged stress is a major risk-factor for psychiatric disorders such as generalized anxiety and major depressive disorder (MDD). Human imaging studies have identified structural and functional abnormalities in the prefrontal cortex of MDD patients, particularly Brodmann’s area 25 (BA25). Further, deep brain stimulation of BA25 reduces...

Stress exposure can produce profound change in physiology and behavior that can impair health and well-being. Of note, stress exposure is linked to anxiety disorders and depression in humans. The widespread impact of these disorders warrants investigation into treatments to mitigate the harmful effects of stress. Pharmacological treatments fail to...

Background The medial prefrontal cortex is necessary for appropriate appraisal of stressful information, as well as coordinating visceral and behavioral processes. However, prolonged stress impairs medial prefrontal cortex function and prefrontal‐dependent behaviors. Additionally, chronic stress induces sympathetic predominance, contributing to hea...

Hypofunction of the prefrontal cortex (PFC) contributes to stress-related neuropsychiatric illnesses. Mechanisms leading to prefrontal hypoactivity remain to be determined. Prior evidence suggests that enhanced activity of parvalbumin (PV) expressing GABAergic interneurons (INs) play a role in chronic stress related pathologies. In this study, the...

Adolescent animals are vulnerable to the effects of stress on brain development. We hypothesized that long-term effects of adolescent chronic stress are mediated by glucocorticoid receptor (GR) signaling. We used a specific GR modulator (CORT108297) to pharmacologically disrupt GR signaling in adolescent rats during exposure to chronic variable str...

Glucocorticoid receptors (GR) have diverse functions relevant to maintenance of homeostasis and adaptation to environmental challenges. Understanding the importance of tissue-specific GR function in physiology and behavior has been hampered by near-ubiquitous localization in brain and body. Here we use CRISPR/Cas9 gene editing to create a condition...

The medial prefrontal cortex (mPFC) is necessary for appropriate appraisal of stressful information, as well as coordinating visceral and behavioral processes. However, prolonged stress impairs mPFC function and prefrontal-dependent behaviors. Additionally, chronic stress induces sympathetic predominance, contributing to health detriments associate...

Adolescent animals are vulnerable to the effects of stress on brain development. We hypothesized that long-term effects of adolescent chronic stress are mediated by glucocorticoid receptor (GR) signaling. We used a specific GR modulator (CORT108297) to pharmacologically disrupt GR signaling in adolescent rats during exposure chronic variable stress...

The medial prefrontal cortex (mPFC) receives information regarding stimuli and appropriately orchestrates neurophysiological, autonomic, and behavioral responses to stress. The cellular and neurochemical heterogeneity of the mPFC and its projections are key to fine-tuning of stress responses and adaptation. Output of the mPFC is mediated by glutama...

Emerging evidence from the preclinical and human research suggests sex differences in response to different types of stress exposure, and that developmental timing, reproductive status, and biological sex are important factors influencing the degree of HPA activation/function. Here we review data regarding: i) sex differences inbehavioral and neura...

Glucocorticoid receptors (GR) have diverse functions relevant to maintenance of homeostasis and adaptation to environmental challenges. Understanding the importance of tissue-specific GR function in physiology and behavior has been hampered by near-ubiquitous localization in brain and body. Here we use CRISPR/Cas9 gene editing to create a condition...

Chronic stress drives behavioral and physiological changes associated with numerous psychiatric disease states. In rodents, the vast majority of chronic stress models involve imposition of external stressors, whereas in humans stress is often driven by internal cues, commonly associated with a sense of loss. We previously exposed groups of rats to...

The medial prefrontal cortex is critical for contextual appraisal, executive function, and goal-directed behavior. Additionally, the infralimbic (IL) subregion of the prefrontal cortex has been implicated in stress responding, mood, and fear memory. However, the specific circuit mechanisms that mediate these effects are largely unknown. To date, IL...

The glucocorticoid receptor (GR) is critically involved in regulation of stress responses [inhibition of the hypothalamic-pituitary-adrenal (HPA) axis], emotional behavior and cognition via interactions with forebrain corticolimbic circuity. Work to date has largely focused on GR actions in forebrain excitatory neurons; however, recent studies sugg...

We investigated the involvement of nitrergic neurotransmission within the paraventricular nucleus of the hypothalamus (PVN) in modulation of local neuronal activation, autonomic and neuroendocrine responses and behavioral consequences of acute restraint stress in rats. Bilateral microinjections of the selective neuronal nitric oxide (NO) synthase (...

Adolescence is a period of active development of stress regulatory neurocircuitry. As a consequence, mechanisms that control the responses to stress are not fully matured during this developmental period, which may result in vulnerability to chronic stress. We hypothesized that adolescent chronic stress would have negative consequences on stress ad...

Clinical data suggest that the neuroendocrine stress response is chronically dysregulated in a subset of patients with temporal lobe epilepsy (TLE), potentially contributing to both disease progression and the development of psychiatric comorbidities such as anxiety and depression. Whether neuroendocrine dysregulation and psychiatric comorbidities...

Adult male C57BL/6J mice have previously been reported to have motor and memory deficits after experimental closed head traumatic brain injury (TBI), without associated gross pathologic damage or neuroimaging changes detectable by magnetic resonance imaging or diffusion tensor imaging protocols. The presence of neurologic deficits, however, suggest...

The prefrontal cortex is necessary for appropriate appraisal and processing of stressful information and is a component of the central network coordinating visceral and behavioral functions. In addition, prolonged stress induces sympathetic predominance, suggesting that prefrontal circuitry may prevent chronic stress‐induced autonomic imbalance. We...

Hindbrain neurons in the nucleus of the solitary tract (NTS) are critical for regulation of hypothalamo-pituitary-adrenocortical (HPA) responses to stress. It is well known that noradrenergic (as well as adrenergic) neurons in the NTS send direct projections to hypophysiotropic corticotropin-releasing hormone (CRH) neurons and control activation of...

Glucocorticoid binding to the intracellular glucocorticoid receptor (GR) stimulates the translocation of the GR from the cytosol to the nucleus, which leads to the transactivation or transrepression of gene transcription. However, multiple lines of evidence suggest that glucocorticoid signaling can also be initiated from the plasma membrane. Here,...

Background: Devising novel prevention strategies for metabolic disorders will depend in part on the careful elucidation of the common pathways for developing metabolic risks. The neurovisceral integration model has proposed that autonomic imbalance plays an important role in the pathway from acute and chronic stress to cardiovascular disease. Thou...

The late adolescent period is characterized by marked neurodevelopmental and endocrine fluctuations in the transition to early adulthood. Adolescents are highly responsive to the external environment, which enhances their ability to adapt and recover from challenges when given nurturing influences, but also makes them vulnerable to aberrant develop...

Ghrelin is a 28-amino acid polypeptide that regulates feeding, glucose metabolism and emotionality (stress, anxiety and depression). Plasma ghrelin circulates as desacyl ghrelin (DAG) or in an acylated form, acyl ghrelin (AG), through the actions of Ghrelin -O-Acyltransferase (GOAT), exhibiting low or high affinity, respectively, for the growth hor...

Adolescence is a period of active development of the brain. During this phase, the mechanisms that regulate stress response are not fully developed and stress response is more intense that in adults. As a consequence, it is believed that adolescent brains are more vulnerable to the effects of chronic stress. This can have particular relevance for t...

Glucocorticoids act via multiple mechanisms to mobilize energy for in maintenance and restoration of homeostasis. In adipose tissue, glucocorticoids can promote lipolysis and facilitate adipocyte differentiation/growth, serving both energy-mobilizing and restorative processes during negative energy balance. Recent data suggest that adipose-dependen...

Chronic stress-associated pathologies frequently associate with alterations in the structure and activity of medial prefrontal cortex (mPFC). However, the influence of infralimbic cortex (IL) projection neurons on HPA axis activity is unknown, as is the involvement of these cells in chronic stress-induced endocrine alterations. In the current study...

The glucagon-like peptide 1 (GLP-1) system plays an important role in blood glucose regulation, in great part through coordinate control of insulin and glucagon secretion. These effects are generally attributed to GLP-1 produced in peripheral sites, principally the intestine. GLP-1 is also produced in hindbrain neurons that signal through GLP-1 rec...

During development, animals are highly vulnerable to the effects of adverse environment. Considering that chronic stress can elicit long-term effects, we hypothesized that adolescent chronic stress causes life-long impairment in the behavioral and physiological adaptations to stressful experiences and this is mediated by the signaling through the g...

The visible burrow system (VBS) is an ethologically relevant social stress model that creates a distinct dominance hierarchy in rats. Randall Sakai's laboratory performed an impressive series of studies documenting the very different impact of VBS exposure on the brain and behavior of dominants (DOM) and subordinates (SUBs). Hierarchy formation cau...

Organismal stress initiates a tightly orchestrated set of responses involving complex physiological and neurocognitive systems. Here, we present evidence for glucagon-like peptide 1 (GLP-1)-mediated paraventricular hypothalamic circuit coordinating the global stress response. The GLP-1 receptor (Glp1r) in mice was knocked down in neurons expressing...

Status epilepticus (SE) induces rapid hyper-activation of the hypothalamo–pituitary–adrenocortical (HPA) axis. HPA axis hyperactivity results in excess exposure to high levels of circulating glucocorticoids, which are associated with neurotoxicity and depression-like behavior. These observations have led to the hypothesis that HPA axis dysfunction...

Organismal stress initiates a tightly orchestrated set of responses involving complex physiological and neurocognitive systems. Here, we present evidence for glucagon-like peptide 1 (GLP-1) mediated paraventricular hypothalamic circuit coordinating the global stress response. The GLP-1 receptor (Glp1r) in mice was knocked down in neurons expressing...

The hypothalamic paraventricular nucleus (PVN) is the primary driver of hypothalamo–pituitary–adrenocortical (HPA) responses. At least part of the role of the PVN is managing the demands of chronic stress exposure. With repeated exposure to stress, hypophysiotrophic corticotropin-releasing hormone (CRH) neurons of the PVN display a remarkable cellu...

3,4-Methylenedioxy-methamphetamine (MDMA) is a unique psychostimulant that continues to be a popular drug of abuse. It has been well documented that MDMA reduces markers of 5-HT axon terminals in rodents, as well as humans. A loss of parvalbumin-immunoreactive (IR) interneurons in the hippocampus following MDMA treatment has only been documented re...

Previous work from our group has shown that chronic homotypic stress (repeated restraint - RR) increases microglial morphological activation in the prefrontal cortex (PFC), while chronic heterotypic stress (chronic variable stress - CVS) produces no such effect. Therefore, we hypothesized that stressor modality would also determine the susceptibili...

Background: Carbon dioxide (CO2) inhalation, a biological challenge and pathologic marker in panic disorder, evokes intense fear and panic attacks in susceptible individuals. The molecular identity and anatomic location of CO2-sensing systems that translate CO2-evoked fear remain unclear. We investigated contributions of microglial acid sensor T c...

Epilepsy is a common neurological disease, affecting 2.4 million people in the US. Among the many different forms of the disease, temporal lobe epilepsy (TLE) is one of the most frequent in adults. Recent studies indicate the presence of a hyperactive hypothalamopituitary- adrenocortical (HPA) axis and elevated levels of glucocorticoids in TLE pati...

In response to stress, defined as a real or perceived threat to homeostasis or well-being, brain systems initiate divergent physiological and behavioral processes that mobilize energy and promote adaptation. The brainstem contains multiple nuclei that engage in autonomic control and reflexive responses to systemic stressors. However, brainstem nucl...

Adolescent animals are known to be highly vulnerable to the effects of adverse environment. It is known that adolescent rat males hyper-respond to chronic variable stress (CVS). Considering that chronic stress can elicit long-term effects, we hypothesized that adolescent chronic stress causes life-long impairment in the behavioral and physiological...

Stress activation of the hypothalamic-pituitary-adrenal (HPA) axis is regulated by rapid glucocorticoid negative feedback. Chronic unpredictable stress animal models recapitulate certain aspects of major depression in humans, which have been attributed to impaired glucocorticoid negative feedback. We tested for an attenuated HPA sensitivity to fast...

The hypothalamo-pituitary-adrenocortical (HPA) axis is required for stress adaptation. Activation of the HPA axis causes secretion of glucocorticoids, which act on multiple organ systems to redirect energy resources to meet real or anticipated demand. The HPA stress response is driven primarily by neural mechanisms, invoking corticotrophin releasin...

Background: Multiple neuropsychiatric disorders, e.g., depression, are linked to imbalances in excitatory and inhibitory neurotransmission and prefrontal cortical dysfunction, and are concomitant with chronic stress. Methods: We used electrophysiologic (n = 5-6 animals, 21-25 cells/group), neuroanatomic (n = 6-8/group), and behavioral (n = 12/gr...

Prolonged and/or frequent exposure to psychological stress responses may lead to deterioration of organs and tissues, predisposing to disease. In agreement with this, chronic psychosocial stress is linked to greater cardiovascular risk, including increased incidence of atherosclerosis, myocardial ischemia, coronary heart disease, and death. Thus th...

Adolescence is a period of substantial neuroplasticity in stress regulatory neurocircuits. Chronic stress exposure during this period leads to long-lasting changes in neuroendocrine function and emotional behaviors, suggesting adolescence may be a critical period for development of stress vulnerability. This study investigated the effects of exposu...

The hypothalamus-pituitary-adrenal (HPA) axis is the main neuroendocrine arm of the stress response, activation of which leads to the production of glucocorticoid hormones. Glucocorticoids are steroid hormones that are secreted from the adrenal cortex, and have a variety of effects on the body, including modulation of the immune system, suppression...

The posterior hypothalamic nucleus (PH) stimulates autonomic stress responses. However, the role of the PH in behavioral correlates of psychiatric illness, such as social and anxiety-like behavior, is largely unexplored, as is the neurochemistry of PH connectivity with limbic and neuroendocrine systems. Thus, the current study tested the hypothesis...

Neuroendocrine responses to stress are mediated by mono- and multisynaptic pathways linking brain regions responsible for cognition, emotion, and homeostatic integration with neurons responsible for ACTH secretion, which are localized primarily in the hypothalamic paraventricular nucleus. Knowledge of stress circuits is continually evolving, fueled...

A history of eating highly palatable foods reduces physiological and emotional responses to stress. For instance, we have previously shown that limited sucrose intake (4 ml of 30 % sucrose twice daily for 14 days) reduces hypothalamic-pituitary-adrenocortical (HPA) axis responses to stress. However, the neural mechanisms underlying stress relief by...

The effects of chronic stress on learning are highly variable across individuals. This variability stems from gene-environment interactions. However, the mechanisms by which stress affects genetic predictors of learning are unclear. Thus, we aim to determine whether the genetic pathways that predict spatial memory performance are altered by previou...

Corticosteroids act classically via cognate nuclear receptors to regulate gene transcription; however, increasing evidence supports rapid, non-transcriptional corticosteroid actions via activation of membrane receptors. Using whole-cell patch clamp recordings in hypothalamic slices from male mouse genetic models, we tested for non-genomic glucocort...

Glucocorticoids act rapidly at the paraventricular nucleus (PVN) to inhibit stress-excitatory neurons and limit excessive glucocorticoid secretion. The signaling mechanism underlying rapid feedback inhibition remains to be determined The present study was designed to test the hypothesis that the canonical glucocorticoid receptors (GR) is required f...

Chronic social subordination is a well-known precipitant of numerous psychiatric and physiological health concerns. In this study, we examine the effects of chronic social stress in the visible burrow system (VBS) on the expression of glutamic acid decarboxylase (GAD) 67 and brain-derived neurotropic factor (BDNF) mRNA in forebrain stress circuitry...

Chronic stress causes hypothalamo-pituitary-adrenal (HPA) axis hyperactivity and cardiovascular dyshomeostasis. Noradrenergic (NA) neurons in the nucleus of the solitary tract (NTS) are considered to play a role in these changes. In this study, we tested the hypothesis that NTS NA A2 neurons are required for cardiovascular and HPA axis responses to...

Responding to real or potential threats in the environment requires the coordination of autonomic, neuroendocrine, and behavioral processes to promote adaptation and survival. These diverging systems necessitate input from the limbic forebrain to integrate and modulate functional output in accordance with contextual demand. In the current review, w...

The melanocortin system directs diverse physiological functions from coat color to body weight homoeostasis. A commonality among melanocortin-mediated processes is that many animals modulate similar processes on a circannual basis in response to longer, summer days, suggesting an underlying link between circadian biology and the melanocortin system...

Glutamate is an important neurotransmitter in regulation of the neural portion of hypothalamus-pituitary-adrenal (HPA) axis activity, and signals through ionotropic and metabotropic receptors. In the current studies we investigated the role of hypothalamic paraventricular group I metabotropic glutamate receptors in regulation of the HPA axis respon...

An individual's genetic background affects their emotional behavior and response to stress. Although studies have been conducted to identify genetic predictors for emotional behavior or stress response, it remains unknown how prior stress history alters the interaction between an individual's genome and their emotional behavior. Therefore, the purp...

Abstract Behavioral modifications for the treatment of obesity, including caloric restriction, have notoriously low long-term success rates relative to bariatric weight-loss surgery. The reasons for the difference in sustained weight loss are not clear. One possibility is that caloric restriction alone activates the stress-responsive hypothalamo-pi...

The incidence of type-2 diabetes (T2D) and the burden it places on individuals, as well as society as a whole, compels research into the causes, factors and progression of this disease. Epidemiological studies suggest that chronic stress exposure may contribute to the development and progression of T2D in human patients. To address the interaction...