Recruitment of Corticotropin-Releasing Hormone (CRH) Neurons in Categorically Distinct Stress Reactions in the Mouse Brain

Corticotropin-releasing hormone (CRH) neurons in the paraventricular hypothalamic nucleus (PVH) are in the position to integrate stress-related information and initiate adaptive neuroendocrine-, autonomic-, metabolic- and behavioral responses. In addition to hypophyseotropic cells, CRH is widely expressed in the CNS, however its involvement in the organization of the stress response is not fully understood. In these experiments, we took advantage of recently available Crh-IRES-Cre;Ai9 mouse line to study the recruitment of hypothalamic and extrahypothalamic CRH neurons in categorically distinct, acute stress reactions. A total of 95 brain regions in the adult male mouse brain have been identified as containing putative CRH neurons with significant expression of tdTomato marker gene. With comparison of CRH mRNA and tdTomato distribution, we found match and mismatch areas. Reporter mice were then exposed to restraint, ether, high salt, lipopolysaccharide and predator odor stress and neuronal activation was revealed by FOS immunocytochemistry. In addition to a core stress system, stressor-specific areas have been revealed to display activity marker FOS. Finally, activation of CRH neurons was detected by colocalization of FOS in tdTomato expressing cells. All stressors resulted in profound activation of CRH neurons in the hypothalamic paraventricular nucleus; however, a differential activation of pattern was observed in CRH neurons in extrahypothalamic regions. This comprehensive description of stress-related CRH neurons in the mouse brain provides a starting point for a systematic functional analysis of the brain stress system and its relation to stress-induced psychopathologies.

[1]  M. Morishima,et al.  Parabrachial-to-parasubthalamic nucleus pathway mediates fear-induced suppression of feeding in male mice , 2022, Nature Communications.

[2]  Ming Li,et al.  A zona incerta-basomedial amygdala circuit modulates aversive expectation in emotional stress-induced aversive learning deficits , 2022, Frontiers in Cellular Neuroscience.

[3]  Patrick O. McGowan,et al.  Hippocampus-Anterior Hypothalamic Circuit Modulates Stress-Induced Endocrine and Behavioral Response , 2022, Frontiers in Neural Circuits.

[4]  A. Yamanaka,et al.  Claustrum mediates bidirectional and reversible control of stress-induced anxiety responses , 2022, Science advances.

[5]  E. Sipos,et al.  Neurochemically distinct populations of the bed nucleus of stria terminalis modulate innate fear response to weak threat evoked by predator odor stimuli , 2021, Neurobiology of Stress.

[6]  Hong Zhou,et al.  Inactivation of Zona Incerta Blocks Social Conditioned Place Aversion and Modulates Post-traumatic Stress Disorder-Like Behaviors in Mice , 2021, Frontiers in Behavioral Neuroscience.

[7]  C. Xavier,et al.  Lateral hypothalamus involvement in control of stress response by bed nucleus of the stria terminalis endocannabinoid neurotransmission in male rats , 2021, Scientific Reports.

[8]  A. D. de Kloet,et al.  Identification of Novel Cross-Talk between the Neuroendocrine and Autonomic Stress Axes Controlling Blood Pressure , 2021, The Journal of Neuroscience.

[9]  S. Gourley,et al.  The stressed orbitofrontal cortex. , 2021, Behavioral neuroscience.

[10]  Reiko Kobayakawa,et al.  Artificial hibernation/life-protective state induced by thiazoline-related innate fear odors , 2021, Communications biology.

[11]  A. Holmes,et al.  Amygdala Circuit Substrates for Stress Adaptation and Adversity , 2021, Biological Psychiatry.

[12]  K. Kohlmeier,et al.  Stress-related endogenous neuropeptides induce neuronal excitation in the Laterodorsal Tegmentum , 2020, European Neuropsychopharmacology.

[13]  Yuta Shima,et al.  A central master driver of psychosocial stress responses in the rat , 2020, Science.

[14]  T. Murphy,et al.  Stress impacts sensory variability through cortical sensory activity motifs , 2020, Translational Psychiatry.

[15]  A. Lawrence,et al.  The effect of acute or repeated stress on the corticotropin releasing factor system in the CRH-IRES-Cre mouse: A validation study , 2019, Neuropharmacology.

[16]  Kong-Joo Lee,et al.  Activity-Regulated Cytoskeleton-Associated Protein (Arc/Arg3.1) is Transiently Expressed after Heat Shock Stress and Suppresses Heat Shock Factor 1 , 2019, Scientific Reports.

[17]  A. Venkataraman,et al.  Modulation of fear generalization by the zona incerta , 2018, Proceedings of the National Academy of Sciences.

[18]  Q. Luo,et al.  A Quantitative Analysis of the Distribution of CRH Neurons in Whole Mouse Brain , 2017, Front. Neuroanat..

[19]  J. Deussing,et al.  CRFR1 in AgRP Neurons Modulates Sympathetic Nervous System Activity to Adapt to Cold Stress and Fasting , 2016, Cell metabolism.

[20]  J. Herman,et al.  GABAergic Signaling within a Limbic-Hypothalamic Circuit Integrates Social and Anxiety-Like Behavior with Stress Reactivity , 2016, Neuropsychopharmacology.

[21]  K. Ressler,et al.  Diversity of Reporter Expression Patterns in Transgenic Mouse Lines Targeting Corticotropin-Releasing Hormone-Expressing Neurons. , 2015, Endocrinology.

[22]  J. McCall,et al.  CRH Engagement of the Locus Coeruleus Noradrenergic System Mediates Stress-Induced Anxiety , 2015, Neuron.

[23]  A. Nuñez,et al.  Synaptic interactions between perifornical lateral hypothalamic area, locus coeruleus nucleus and the oral pontine reticular nucleus are implicated in the stage succession during sleep-wakefulness cycle , 2013, Front. Neurosci..

[24]  J. Bains,et al.  Characterization of Corticotropin-Releasing Hormone neurons in the Paraventricular Nucleus of the Hypothalamus of Crh-IRES-Cre Mutant Mice , 2013, PloS one.

[25]  J. Herman,et al.  Send Orders of Reprints at Reprints@benthamscience.net Mechanisms in the Bed Nucleus of the Stria Terminalis Involved in Control of Autonomic and Neuroendocrine Functions: a Review , 2022 .

[26]  Y. Taché,et al.  Neuropeptides and Stress , 2012, Hans Selye Symposia on Neuroendocrinology and Stress.

[27]  C. Berridge,et al.  Corticotropin-Releasing Factor Acting at the Locus Coeruleus Disrupts Thalamic and Cortical Sensory-Evoked Responses , 2012, Neuropsychopharmacology.

[28]  S. Nelson,et al.  A Resource of Cre Driver Lines for Genetic Targeting of GABAergic Neurons in Cerebral Cortex , 2011, Neuron.

[29]  Hidenori Suzuki,et al.  Chronic stress enhances synaptic plasticity due to disinhibition in the anterior cingulate cortex and induces hyper-locomotion in mice , 2010, Neuropharmacology.

[30]  Allan R. Jones,et al.  A robust and high-throughput Cre reporting and characterization system for the whole mouse brain , 2009, Nature Neuroscience.

[31]  G. Koob.  A Role for Brain Stress Systems in Addiction , 2008, Neuron.

[32]  J. D. McGaugh,et al.  Corticotropin-Releasing Factor in the Basolateral Amygdala Enhances Memory Consolidation via an Interaction with the β-Adrenoceptor–cAMP Pathway: Dependence on Glucocorticoid Receptor Activation , 2008, The Journal of Neuroscience.

[33]  K. Kovács,et al.  Measurement of Immediate‐Early Gene Activation‐ c‐fos and Beyond , 2008, Journal of neuroendocrinology.

[34]  Paul E. Sawchenko,et al.  Regional Differentiation of the Medial Prefrontal Cortex in Regulating Adaptive Responses to Acute Emotional Stress , 2006, The Journal of Neuroscience.

[35]  K. Short,et al.  A stress-induced anxious state in male rats: Corticotropin-releasing hormone induces persistent changes in associative learning and startle reactivity , 2005, Biological Psychiatry.

[36]  L. Jacobson,et al.  Chronic treatment with the monoamine oxidase inhibitor phenelzine increases hypothalamic-pituitary-adrenocortical activity in male C57BL/6 mice: relevance to atypical depression. , 2005, Endocrinology.

[37]  Stephen C. Heinrichs,et al.  Corticotropin-Releasing Factor in Brain: A Role in Activation, Arousal, and Affect Regulation , 2004, Journal of Pharmacology and Experimental Therapeutics.

[38]  Z. Tóth,et al.  Role of hypothalamic inputs in maintaining pituitary-adrenal responsiveness in repeated restraint. , 2003, American journal of physiology. Endocrinology and metabolism.

[39]  M. Zaretskaia,et al.  The dorsomedial hypothalamus and the response to stress Part renaissance, part revolution , 2002, Pharmacology Biochemistry and Behavior.

[40]  N. Kalin,et al.  Acute stress-induced increases in thalamic CRH mRNA are blocked by repeated stress exposure , 2001, Brain Research.

[41]  C. Dayas,et al.  Stressor categorization: acute physical and psychological stressors elicit distinctive recruitment patterns in the amygdala and in medullary noradrenergic cell groups , 2001, The European journal of neuroscience.

[42]  N. Kalin,et al.  Corticotropin-releasing hormone messenger RNA distribution and stress-induced activation in the thalamus , 2001, Neuroscience.

[43]  M. Palkovits,et al.  Stressor specificity of central neuroendocrine responses: implications for stress-related disorders. , 2001, Endocrine reviews.

[44]  D. Baker,et al.  Corticotropin-releasing hormone in depression and post-traumatic stress disorder , 2001, Peptides.

[45]  P. Sawchenko,et al.  Circuits and mechanisms governing hypothalamic responses to stress: a tale of two paradigms. , 2000, Progress in brain research.

[46]  I. Ábrahám,et al.  Postnatal handling alters the activation of stress‐related neuronal circuitries , 2000, The European journal of neuroscience.

[47]  E. V. Van Bockstaele,et al.  Amygdaloid Corticotropin‐Releasing Factor Targets Locus Coeruleus Dendrites: Substrate for the Co‐ordination of Emotional and Cognitive Limbs of the Stress Response , 1998, Journal of neuroendocrinology.

[48]  P. Sawchenko,et al.  Hypothalamic effector neurons and extended circuitries activated in “neurogenic” stress: A comparison of footshock effects exerted acutely, chronically, and in animals with controlled glucocorticoid levels , 1998, The Journal of comparative neurology.

[49]  S. Watson.  Neuroendocrine and Behavioral Responses and Brain Pattern of c‐fos Induction Associated with Audiogenic Stress , 1997, Journal of neuroendocrinology.

[50]  H. Akil,et al.  Lesions of the Medial Geniculate Nuclei Specifically Block Corticosterone Release and Induction of c-fos mRNA in the Forebrain Associated with Audiogenic Stress in Rats , 1997, The Journal of Neuroscience.

[51]  Florian Holsboer,et al.  Long-Term Intracerebroventricular Infusion of Corticotropin-Releasing Hormone Alters Neuroendocrine, Neurochemical, Autonomic, Behavioral, and Cytokine Responses to a Systemic Inflammatory Challenge , 1997, The Journal of Neuroscience.

[52]  S. Watson,et al.  Fos expression in forebrain afferents to the hypothalamic paraventricular nucleus following swim stress , 1996, The Journal of comparative neurology.

[53]  P. Sawchenko,et al.  Distinct mechanisms underlie activation of hypothalamic neurosecretory neurons and their medullary catecholaminergic afferents in categorically different stress paradigms. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[54]  P. Sawchenko,et al.  Sequence of stress-induced alterations in indices of synaptic and transcriptional activation in parvocellular neurosecretory neurons , 1996, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[55]  P. Sawchenko,et al.  A functional anatomical analysis of central pathways subserving the effects of interleukin-1 on stress-related neuroendocrine neurons , 1994, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[56]  S. Rivest,et al.  Stress and Interleukin‐1 β‐Induced Activation of c‐fos, NGFI‐B ann CRF Gene Expression in the Hypothalamic PVN: Comparison Between Sprague‐Dawley, Fisher‐344 and Lewis Rats , 1994, Journal of neuroendocrinology.

[57]  P. Sawchenko,et al.  A comparison of two immediate-early genes, c-fos and NGFI-B, as markers for functional activation in stress-related neuroendocrine circuitry. , 1993 .

[58]  S. Korte,et al.  Central Actions of Corticotropin-Releasing Hormone (CRH) on Behavioral, Neuroendocrine, and Cardiovascular Regulation: Brain Corticoid Receptor Involvement , 1993, Hormones and Behavior.

[59]  Craig W. Berridge,et al.  Physiological and behavioral responses to corticotropin-releasing factor administration: is CRF a mediator of anxiety or stress responses? , 1990, Brain Research Reviews.

[60]  S. Lightman,et al.  Corticotrophin‐releasing factor, vasopressin and pro‐opiomelanocortin mRNA responses to stress and opiates in the rat. , 1988, The Journal of physiology.

[61]  I. Merchenthaler,et al.  Corticotropin releasing factor (CRF)-like immunoreactivity in the rat central nervous system. Extrahypothalamic distribution , 1984, Peptides.

[62]  M. Palkovits,et al.  Immunoreactive corticotropin-releasing hormone in the hypothalamoinfundibular tract. , 1983, Neuroendocrinology.

[63]  W. Vale,et al.  Characterization of a 41-residue ovine hypothalamic peptide that stimulates secretion of corticotropin and beta-endorphin , 1981 .

[64]  B. Roland,et al.  The paraventricular nucleus of the hypothalamus and the functional neuroanatomy of visceromotor responses to stress. , 1996, Progress in brain research.

[65]  T. Curran,et al.  Stimulus-transcription coupling in the nervous system: involvement of the inducible proto-oncogenes fos and jun. , 1991, Annual review of neuroscience.

[66]  A. Silverman,et al.  Modification of Hypothalamic Neurons by Behavioral Stress , 1989 .

[67]  L. Swanson,et al.  Organization of ovine corticotropin-releasing factor immunoreactive cells and fibers in the rat brain: an immunohistochemical study. , 1983, Neuroendocrinology.