Neural Regulation of the Stress Response: The Many Faces of Feedback

“Although the permissive actions of MR maintain cellular responses to GCs, only stress levels of GCs extensively bind GR, which is necessary for the inhibition of HPA stress responses (Reul and de Kloet 1985; de Kloet and Reul 1987; Boyle et al. 2005; de Kloet et al. 2005).”

“…correlate with altered activation or volume of the prefrontal cortex, amygdala, and hippocampus, suggesting that the disease processes involve the anticipatory stress response (Drevets 1999; Mayberg et al. 2005; Yehuda and LeDoux 2007; Krishnan and Nestler 2010; Myers-Schulz and Koenigs 2011).”

“These neurons project to blood vessels in the median eminence, where they release adrenocorticotropin (ACTH) secretagogues, the most potent of which are corticotropin-releasing hormone (CRH) and arginine vasopressin (Vale et al. 1981; Swanson et al. 1983).”

“, the nucleus of the solitary tract (NTS), circumventricular organs) (Ulrich-Lai and Herman 2009).”

“The MR has a very high affinity for endogenous GCs and regulates circadian secretory rhythms and ultradian pulsatility (de Kloet et al. 1998; de Kloet and Sarabdjitsingh 2008).”

“Keywords Hypothalamo–pituitary–adrenocortical axis Corticotropin-releasing hormone Corticosterone Glucocorticoid receptor Hypothalamus Amygdala Prefrontal cortex”

“These neurons project to blood vessels in the median eminence, where they release adrenocorticotropin (ACTH) secretagogues, the most potent of which are corticotropin-releasing hormone (CRH) and arginine vasopressin (Vale et al. 1981; Swanson et al. 1983).”

“…al. 1991; Roozendaal et al. 1992; Feldman et al. 1994; Feldman and Weidenfeld 1998; Shepard et al. 2003), although there is considerable functional differentiation among individual amygdalar regions (Dunn and Whitener 1986; Swanson and Petrovich 1998; Sah et al. 2003; Ulrich-Lai and Herman 2009).”

“Accumulating evidence suggests that heightened GCs contribute to visceral obesity, especially in the propensity to consume rewarding foods (Adam and Epel 2007).”

“These brain structures have no direct inputs to the PVN and require synaptic relays in subcortical structures (Herman et al. 2003).”

“…ventromedial hypothalamus, vSub ventral subiculum, ? denotes excitation and - inhibition subcortical ilPFC projections differ substantially from those of the plPFC, targeting known stress-excitatory regions such as the central nucleus of the amygdala (CeA) and NTS (Hurley et al. 1991; Vertes 2004).”

“Dallman et al. (2003) propose that recruitment of amygdalar CRH may be a deleterious consequence of elevated GC release during chronic stress or stress-related diseases.”

“restraint (Diorio et al. 1993), indicating that the inhibitory effect of the plPFC is at least in part GR-dependent.”

“Although the basolateral amygdala (BLA) is activated by both psychogenic and systemic stressors (Cullinan et al. 1995; Jones et al. 2011), relatively few studies have examined the role of this area in GC secretion.”

“Arachidonoyl ethanolamide (also known as anandamide) and 2-arachidonoylglycerol, eCBs rapidly produced in the PVN following GC exposure, act as dendritic retrograde messengers to mediate GSE (Di et al. 2003; Malcher-Lopes et al. 2006; Evanson et al. 2010).”

“…correlate with altered activation or volume of the prefrontal cortex, amygdala, and hippocampus, suggesting that the disease processes involve the anticipatory stress response (Drevets 1999; Mayberg et al. 2005; Yehuda and LeDoux 2007; Krishnan and Nestler 2010; Myers-Schulz and Koenigs 2011).”

“The output of the basolateral amygdala is predominantly glutamatergic, suggesting that modulation of GC responses is mediated by excitatory PVN-projecting neurons as well as extensive interactions with other regions of the amygdala (Krettek and Price 1977; Pare et al. 1995; Dong et al. 2001a).”

“…ventromedial hypothalamus, vSub ventral subiculum, ? denotes excitation and - inhibition subcortical ilPFC projections differ substantially from those of the plPFC, targeting known stress-excitatory regions such as the central nucleus of the amygdala (CeA) and NTS (Hurley et al. 1991; Vertes 2004).”

“The PVN receives a large input from brainstem noradrenergic and adrenergic neurons of the NTS and C1–C3 (Cunningham and Sawchenko 1988; Cunningham et al. 1990).”

“There is also a specific projection from the CeA to the anterolateral BST, a stress-excitatory region that innervates the PVN (Dong et al. 2001a; Dong and Swanson 2004a; Choi et al. 2007).”

“Multiple limbic brain regions express GR and contribute to feedback integration (McEwen et al. 1968; Reul and de Kloet 1985; Boyle et al. 2005).”

“no direct interactions with medial parvocellular PVN neurons, requiring intermediary neurons to relay their influence on CRH release (Sawchenko and Swanson 1983; Ulrich-Lai and Herman 2009).”

“PVN-projecting neurons in the NTS also contain peptide neuromodulators (e.g., glucagon-like peptide-1 (GLP-1), neuropeptide Y) that are HPA axis excitatory (Sawchenko et al. 1985; Harfstrand 1987; Merchenthaler et al. 1999; Tauchi et al. 2008).”

“Further, GCs can negatively affect processes governing dendritic plasticity, neurogenesis, and neuronal viability (Sapolsky et al. 1986; Pham et al. 2003; Radley et al. 2008).”

“Adrenocorticotropin secretion from the anterior pituitary then leads to the synthesis and release of GCs from the adrenal cortex (Dallman and Jones 1973; Dallman et al. 1987).”

“…correlate with altered activation or volume of the prefrontal cortex, amygdala, and hippocampus, suggesting that the disease processes involve the anticipatory stress response (Drevets 1999; Mayberg et al. 2005; Yehuda and LeDoux 2007; Krishnan and Nestler 2010; Myers-Schulz and Koenigs 2011).”

“The GR is densely expressed in the PVN as well as numerous brain regions implicated in HPA axis regulation, all of which may contribute to feedback regulation (Reul and de Kloet 1985; de Kloet and Reul 1987; Jankord and Herman 2008).”

“The GR is densely expressed in the PVN as well as numerous brain regions implicated in HPA axis regulation, all of which may contribute to feedback regulation (Reul and de Kloet 1985; de Kloet and Reul 1987; Jankord and Herman 2008).”

“…correlate with altered activation or volume of the prefrontal cortex, amygdala, and hippocampus, suggesting that the disease processes involve the anticipatory stress response (Drevets 1999; Mayberg et al. 2005; Yehuda and LeDoux 2007; Krishnan and Nestler 2010; Myers-Schulz and Koenigs 2011).”

“Hence, inhibition is thought to be mediated by activation of PVN-projecting GABAergic neurons in the BST, POA, DMH, and peri-PVN region (Cullinan et al. 1993; Choi et al. 2007; Radley and Sawchenko 2011).”

“Lesions of these neurons attenuate reflexive HPA axis responses to stressors, while adrenergic receptor stimulation activates CRH and ACTH secretion, indicating that norepinephrine and epinephrine are necessary and sufficient for HPA axis activation (Plotsky 1987; Plotsky et al. 1989).”

“There is also a specific projection from the CeA to the anterolateral BST, a stress-excitatory region that innervates the PVN (Dong et al. 2001a; Dong and Swanson 2004a; Choi et al. 2007).”

“The CeA appears to be involved in activation of the HPA axis in response to systemic but not psychogenic stressors (Dayas et al. 1999; Xu et al. 1999; Dayas et al. 2001).”

“Cannabinoid receptors are predominately localized in presynaptic terminals, and CB1 antagonism or knockout leads to elevated CRH expression in the PVN and increased plasma ACTH and CORT (Patel et al. 2004; Cota et al. 2007; Ginsberg et al. 2010; Hill and McEwen 2010).”

“The hippocampus is involved in terminating anticipatory HPA axis responses, consistent with its role in memory and emotion processing (Herman et al. 1989; Cullinan et al. 1993; Mueller et al. 2004; Radley and Sawchenko 2011).”

“Lesion studies indicate that the more ventral components of the mPFC (infralimbic (il) PFC) may be involved in stress excitation (Sullivan and Gratton 1998, 1999; Radley et al. 2006).”

“There is also a specific projection from the CeA to the anterolateral BST, a stress-excitatory region that innervates the PVN (Dong et al. 2001a; Dong and Swanson 2004a; Choi et al. 2007).”

“…regions of the BST inhibit HPA axis responses to stress whereas anterior BST neurons provide excitatory input to the PVN, a heterogeneity that may be related to differential limbic innervation of these regions (Herman et al. 1994; Dong et al. 2001b; Dong and Swanson 2004b, 2006; Choi et al. 2007).”

“However, direct serotonin input to the PVN is somewhat limited as the majority of serotoninergic fibers terminate in the peri-PVN (Sawchenko et al. 1983).”

“Multiple limbic brain regions express GR and contribute to feedback integration (McEwen et al. 1968; Reul and de Kloet 1985; Boyle et al. 2005).”

“Lesion studies indicate that the more ventral components of the mPFC (infralimbic (il) PFC) may be involved in stress excitation (Sullivan and Gratton 1998, 1999; Radley et al. 2006).”

“Further, GCs can negatively affect processes governing dendritic plasticity, neurogenesis, and neuronal viability (Sapolsky et al. 1986; Pham et al. 2003; Radley et al. 2008).”

“The raphe nuclei also heavily innervate limbic structures including the hippocampus, prefrontal cortex, and amygdala (Lowry 2002), suggesting that serotonin has both direct and indirect effects on HPA axis regulation.”

“There is also a specific projection from the CeA to the anterolateral BST, a stress-excitatory region that innervates the PVN (Dong et al. 2001a; Dong and Swanson 2004a; Choi et al. 2007).”

“GABAergic inputs to the PVN originate in hypothalamic nuclei involved in homeostatic regulation, including the dorsomedial hypothalamus (DMH), preoptic area (POA), arcuate nucleus, and lateral hypothalamus (Roland and Sawchenko 1993).”

“The peri-PVN region contains large numbers of GABAergic neurons, some of which project into the PVN proper (Boudaba et al. 1996).”

“…correlate with altered activation or volume of the prefrontal cortex, amygdala, and hippocampus, suggesting that the disease processes involve the anticipatory stress response (Drevets 1999; Mayberg et al. 2005; Yehuda and LeDoux 2007; Krishnan and Nestler 2010; Myers-Schulz and Koenigs 2011).”

“The PVN receives a large input from brainstem noradrenergic and adrenergic neurons of the NTS and C1–C3 (Cunningham and Sawchenko 1988; Cunningham et al. 1990).”

“Lesions of these neurons attenuate reflexive HPA axis responses to stressors, while adrenergic receptor stimulation activates CRH and ACTH secretion, indicating that norepinephrine and epinephrine are necessary and sufficient for HPA axis activation (Plotsky 1987; Plotsky et al. 1989).”

“Arachidonoyl ethanolamide (also known as anandamide) and 2-arachidonoylglycerol, eCBs rapidly produced in the PVN following GC exposure, act as dendritic retrograde messengers to mediate GSE (Di et al. 2003; Malcher-Lopes et al. 2006; Evanson et al. 2010).”

“GCs localized to the CeA increase CRH mRNA in the CeA, anterolateral BST, and PVN (Shepard et al. 2000, 2003, 2006).”

“The CeA appears to be involved in activation of the HPA axis in response to systemic but not psychogenic stressors (Dayas et al. 1999; Xu et al. 1999; Dayas et al. 2001).”

“There is also a specific projection from the CeA to the anterolateral BST, a stress-excitatory region that innervates the PVN (Dong et al. 2001a; Dong and Swanson 2004a; Choi et al. 2007).”

“…regions of the BST inhibit HPA axis responses to stress whereas anterior BST neurons provide excitatory input to the PVN, a heterogeneity that may be related to differential limbic innervation of these regions (Herman et al. 1994; Dong et al. 2001b; Dong and Swanson 2004b, 2006; Choi et al. 2007).”

“ameliorate symptoms in patients with psychotic depression (Belanoff et al. 2001), suggesting that the GR may be a”

“GCs rapidly inhibit PVN CRH neurons by way of a membrane-associated GR (mGR) that suppresses excitatory synaptic inputs to the PVN (Di et al. 2003, 2005; Tasker and Herman 2011).”

“GCs rapidly inhibit PVN CRH neurons by way of a membrane-associated GR (mGR) that suppresses excitatory synaptic inputs to the PVN (Di et al. 2003, 2005; Tasker and Herman 2011).”

“Despite GC hyposecretion, PTSD patients may actually have prolonged GC exposure following stress due to reduced activity of GC-metabolizing enzymes (Yehuda et al. 2009; Yehuda and Seckl 2011).”

“Indeed, anatomical studies suggest that plPFC activates inhibitory relays in the BST (Radley et al. 2009).”

“Arachidonoyl ethanolamide (also known as anandamide) and 2-arachidonoylglycerol, eCBs rapidly produced in the PVN following GC exposure, act as dendritic retrograde messengers to mediate GSE (Di et al. 2003; Malcher-Lopes et al. 2006; Evanson et al. 2010).”

“This region also receives rich input from hypothalamic cell groups, serotonin neurons, and limbic structures, suggesting that this area may play a role in limiting information coming into the PVN (Cole and Sawchenko 2002; Herman et al. 2002).”

“Numerous studies indicate that dorsal components of the mPFC (prelimbic (pl) PFC) inhibit HPA axis responses (Diorio et al. 1993; Figueiredo et al. 2003; Boyle et al. 2005; Radley et al. 2006, 2009).”

“Hence, inhibition is thought to be mediated by activation of PVN-projecting GABAergic neurons in the BST, POA, DMH, and peri-PVN region (Cullinan et al. 1993; Choi et al. 2007; Radley and Sawchenko 2011).”

“Adrenocorticotropin secretion from the anterior pituitary then leads to the synthesis and release of GCs from the adrenal cortex (Dallman and Jones 1973; Dallman et al. 1987).”

“Cannabinoid receptors are predominately localized in presynaptic terminals, and CB1 antagonism or knockout leads to elevated CRH expression in the PVN and increased plasma ACTH and CORT (Patel et al. 2004; Cota et al. 2007; Ginsberg et al. 2010; Hill and McEwen 2010).”

“In general, PVN afferent neurons are localized to regions known to receive inputs from somatic nociceptors, visceral afferents, and/or humoral sensory pathways (Kiss et al. 1996; Li et al. 1996).”

“…feedback is supported by the dense expression of GRs in the hippocampus (Reul and de Kloet 1985), as well as functional studies demonstrating diminished feedback efficacy following hippocampal lesions or local GR inactivation (van Haarst et al. 1997; Herman and Mueller 2006; Mueller et al. 2006).”

“…regions of the BST inhibit HPA axis responses to stress whereas anterior BST neurons provide excitatory input to the PVN, a heterogeneity that may be related to differential limbic innervation of these regions (Herman et al. 1994; Dong et al. 2001b; Dong and Swanson 2004b, 2006; Choi et al. 2007).”

“In addition, sensitization of reward pathways due to aberrant HPA axis activity has been proposed to drive vulnerability to addictive disorders, as GCs promote perseverance of addictive behavior (de Jong and de Kloet 2004; Uhart and Wand 2009; Frank et al. 2011).”

“Of the known stressresponsive thalamic nuclei, the paraventricular thalamus appears to play a major role in integrating HPA axis responses, mediating both habituation to familiar stressors and sensitization to novel stressors (Bhatnagar et al. 2002; Jaferi and Bhatnagar 2006).”

“Stress is also a prominent risk factor for neurological conditions including epilepsy, Parkinson’s disease, Alzheimer’s disease, and chronic pain, suggesting that GCs play a role in the onset and progression of these disorders (Smith et al. 2002; Myers et al. 2007; Sotiropoulos et al. 2008; Kanner 2009; McEwen and Kal…”

“Nongenomic regulation of PVN neurons is mediated by intracellular signaling networks promoting the synthesis of endocannabinoids (eCBs) in the PVN (Di et al. 2009)”

“MDD is commonly associated with hypercortisolemia, whereas PTSD is frequently linked to GC hyposecretion (Yehuda et al. 2004; Radley et al. 2011; Yehuda and Seckl 2011).”

“Most projection neurons of the central and medial amygdala are primarily GABAergic, and both regions project heavily to the BST and POA, which contain populations of GABAergic PVN-projecting neurons (Prewitt and Herman 1998; Sah et al. 2003).”

“Cannabinoid receptors are predominately localized in presynaptic terminals, and CB1 antagonism or knockout leads to elevated CRH expression in the PVN and increased plasma ACTH and CORT (Patel et al. 2004; Cota et al. 2007; Ginsberg et al. 2010; Hill and McEwen 2010).”

“There is electron microscopy and neurochemical evidence for GR localization to neuronal membranes, in particular postsynaptic membranes, supporting an alternative role for the so-called nuclear receptor (Johnson et al. 2005; Komatsuzaki et al. 2005; Wang and Wang 2009; Prager et al. 2010).”

“Cannabinoid receptors are predominately localized in presynaptic terminals, and CB1 antagonism or knockout leads to elevated CRH expression in the PVN and increased plasma ACTH and CORT (Patel et al. 2004; Cota et al. 2007; Ginsberg et al. 2010; Hill and McEwen 2010).”

“GCs are known to have effects on RNA stability in vitro, and may utilize this mechanism to limit excitation of the PVN following stress (Stellato 2004).”

“However, the mechanisms underlying nongenomic feedback were not understood until recently (Dallman and Yates 1969; Dallman 2005).”

“Similar to ilPFC, the amygdala provides excitation of HPA axis responses (Roozendaal et al. 1991; Van de Kar et al. 1991; Roozendaal et al. 1992; Feldman et al. 1994; Feldman and Weidenfeld 1998; Shepard et al. 2003), although there is considerable functional differentiation among individual…”

“…knockout mice, which sustain GR deletion in the hippocampus (as well as prefrontal cortex and basolateral amygdala), also show delayed inhibition of the HPA axis response to psychogenic (but not systemic) stressors, further suggesting a role for the hippocampal GR in feedback (Furay et al. 2008).”

“Furthermore, the GR appears vital for normal function of amygdala circuits, as mice with specific disruption of the CeA GR have deficiencies in fear conditioning (Kolber et al. 2008).”

“This region also receives rich input from hypothalamic cell groups, serotonin neurons, and limbic structures, suggesting that this area may play a role in limiting information coming into the PVN (Cole and Sawchenko 2002; Herman et al. 2002).”

“The output of the basolateral amygdala is predominantly glutamatergic, suggesting that modulation of GC responses is mediated by excitatory PVN-projecting neurons as well as extensive interactions with other regions of the amygdala (Krettek and Price 1977; Pare et al. 1995; Dong et al. 2001a).”

“…feedback is supported by the dense expression of GRs in the hippocampus (Reul and de Kloet 1985), as well as functional studies demonstrating diminished feedback efficacy following hippocampal lesions or local GR inactivation (van Haarst et al. 1997; Herman and Mueller 2006; Mueller et al. 2006).”

“3), amygdaloid GRs can stimulate HPA responses (Beaulieu et al. 1986, 1987; Shepard et al. 2003; Myers and Greenwood-Van Meerveld 2011).”

“…al. 1991; Roozendaal et al. 1992; Feldman et al. 1994; Feldman and Weidenfeld 1998; Shepard et al. 2003), although there is considerable functional differentiation among individual amygdalar regions (Dunn and Whitener 1986; Swanson and Petrovich 1998; Sah et al. 2003; Ulrich-Lai and Herman 2009).”

“Similar to ilPFC, the amygdala provides excitation of HPA axis responses (Roozendaal et al. 1991; Van de Kar et al. 1991; Roozendaal et al. 1992; Feldman et al. 1994; Feldman and Weidenfeld 1998; Shepard et al. 2003), although there is considerable functional differentiation among individual…”

“The lateral septum inhibits HPA axis stress responses, and the anatomy of the septal region suggests interactions with hypothalamic and brainstem regions projecting to the PVN (Staiger and Nurnberger 1991; Singewald et al. 2011).”

“There are known inhibitory actions of GCs (albeit at high physiologic levels) on ACTH release by the pituitary (Miller et al. 1992).”

“3), amygdaloid GRs can stimulate HPA responses (Beaulieu et al. 1986, 1987; Shepard et al. 2003; Myers and Greenwood-Van Meerveld 2011).”

“MDD is commonly associated with hypercortisolemia, whereas PTSD is frequently linked to GC hyposecretion (Yehuda et al. 2004; Radley et al. 2011; Yehuda and Seckl 2011).”

“…the amygdala provides excitation of HPA axis responses (Roozendaal et al. 1991; Van de Kar et al. 1991; Roozendaal et al. 1992; Feldman et al. 1994; Feldman and Weidenfeld 1998; Shepard et al. 2003), although there is considerable functional differentiation among individual amygdalar regions (Dunn…”

“The CeA appears to be involved in activation of the HPA axis in response to systemic but not psychogenic stressors (Dayas et al. 1999; Xu et al. 1999; Dayas et al. 2001).”

“Of the known stressresponsive thalamic nuclei, the paraventricular thalamus appears to play a major role in integrating HPA axis responses, mediating both habituation to familiar stressors and sensitization to novel stressors (Bhatnagar et al. 2002; Jaferi and Bhatnagar 2006).”

“Lesion studies indicate that the more ventral components of the mPFC (infralimbic (il) PFC) may be involved in stress excitation (Sullivan and Gratton 1998, 1999; Radley et al. 2006).”

“In addition, sensitization of reward pathways due to aberrant HPA axis activity has been proposed to drive vulnerability to addictive disorders, as GCs promote perseverance of addictive behavior (de Jong and de Kloet 2004; Uhart and Wand 2009; Frank et al. 2011).”

“Similar to ilPFC, the amygdala provides excitation of HPA axis responses (Roozendaal et al. 1991; Van de Kar et al. 1991; Roozendaal et al. 1992; Feldman et al. 1994; Feldman and Weidenfeld 1998; Shepard et al. 2003), although there is considerable functional differentiation among individual…”

“Conversely, the medial amygdala may be selectively involved in generating anticipatory responses (Dayas et al. 1999, 2001; Ma and Morilak 2005; Solomon et al. 2010).”

“1998) and stressinduced CeA CRH release is blocked by pretreatment with a GR antagonist (Cook 2002).”

“GCs localized to the CeA increase CRH mRNA in the CeA, anterolateral BST, and PVN (Shepard et al. 2000, 2003, 2006).”

“Stress is also a prominent risk factor for neurological conditions including epilepsy, Parkinson’s disease, Alzheimer’s disease, and chronic pain, suggesting that GCs play a role in the onset and progression of these disorders (Smith et al. 2002; Myers et al. 2007; Sotiropoulos et al. 2008; Kanner 2009; McEwen and Kal…”

“However, regional heterogeneity of BST effects on the HPA axis may be limited to acute stress as both the anterior and posterior BST provide inhibition of GC responses following chronic stress (Choi et al. 2008a, b).”

“For example, a high proportion of depressed individuals fail to suppress HPA axis secretory activity following exogenous GC (dexamethasone) treatment, indicating a loss of feedback sensitivity (Carroll et al. 1980).”

“However, regional heterogeneity of BST effects on the HPA axis may be limited to acute stress as both the anterior and posterior BST provide inhibition of GC responses following chronic stress (Choi et al. 2008a, b).”

“Stress is also a prominent risk factor for neurological conditions including epilepsy, Parkinson’s disease, Alzheimer’s disease, and chronic pain, suggesting that GCs play a role in the onset and progression of these disorders (Smith et al. 2002; Myers et al. 2007; Sotiropoulos et al. 2008; Kanner 2009; McEwen and Kal…”

“The PVN also receives input from hypothalamic neuropeptide (e.g., CRH, alpha-melanoctye stimulation hormone) and glutamate expressing neurons (Ziegler and Herman 2000; Zhang and Felder 2004; Rinaman 2007; Ulrich-Lai et al. 2011).”

“However, lesions of the BLA dampen HPA axis responses to psychogenic stress (Bhatnagar et al. 2004) while intra-BLA administration of CRH increases GC secretion (Daniels et al. 2004), indicating this area may also provide feedforward regulation of the HPA axis.”

“Cannabinoid receptors are predominately localized in presynaptic terminals, and CB1 antagonism or knockout leads to elevated CRH expression in the PVN and increased plasma ACTH and CORT (Patel et al. 2004; Cota et al. 2007; Ginsberg et al. 2010; Hill and McEwen 2010).”

“The vast majority of these patients exhibit obesity, hypertension, impaired glucose tolerance, diabetes, and dyslipidemia (Sharma and Nieman 2011).”

“Despite GC hyposecretion, PTSD patients may actually have prolonged GC exposure following stress due to reduced activity of GC-metabolizing enzymes (Yehuda et al. 2009; Yehuda and Seckl 2011).”

“There is electron microscopy and neurochemical evidence for GR localization to neuronal membranes, in particular postsynaptic membranes, supporting an alternative role for the so-called nuclear receptor (Johnson et al. 2005; Komatsuzaki et al. 2005; Wang and Wang 2009; Prager et al. 2010).”

“GABAergic inputs to the PVN originate in hypothalamic nuclei involved in homeostatic regulation, including the dorsomedial hypothalamus (DMH), preoptic area (POA), arcuate nucleus, and lateral hypothalamus (Roland and Sawchenko 1993).”

“Several reports implicate midline thalamic nuclei in HPA axis regulation, likely communicated via hypothalamic nuclei (Jaferi et al. 2003).”

“The hippocampus is involved in terminating anticipatory HPA axis responses, consistent with its role in memory and emotion processing (Herman et al. 1989; Cullinan et al. 1993; Mueller et al. 2004; Radley and Sawchenko 2011).”

“There is electron microscopy and neurochemical evidence for GR localization to neuronal membranes, in particular postsynaptic membranes, supporting an alternative role for the so-called nuclear receptor (Johnson et al. 2005; Komatsuzaki et al. 2005; Wang and Wang 2009; Prager et al. 2010).”

“These inputs are predominately excitatory and serve to activate the HPA axis in response to homeostatic imbalance (Ziegler and Herman 2000; Bartanusz et al. 2004).”

“The PVN also receives input from hypothalamic neuropeptide (e.g., CRH, alpha-melanoctye stimulation hormone) and glutamate expressing neurons (Ziegler and Herman 2000; Zhang and Felder 2004; Rinaman 2007; Ulrich-Lai et al. 2011).”

“, glucagon-like peptide-1 (GLP-1), neuropeptide Y) that are HPA axis excitatory (Sawchenko et al. 1985; Harfstrand 1987; Merchenthaler et al. 1999; Tauchi et al. 2008).”

“Keywords Hypothalamo–pituitary–adrenocortical axis Corticotropin-releasing hormone Corticosterone Glucocorticoid receptor Hypothalamus Amygdala Prefrontal cortex”

“Acute activation of the plPFC reduces GC secretion after psychogenic stress (Jones et al. 2011) and restraint-activated neurons of the plPFC express GR (Ostrander et al. 2003), suggesting that GC-sensitive neurons are engaged by stressors.”

“Numerous other organ systems with the capacity to signal into the CNS (e.g., adipose tissue) express GR (Bronnegard et al. 1990).”

“Conversely, the medial amygdala may be selectively involved in generating anticipatory responses (Dayas et al. 1999, 2001; Ma and Morilak 2005; Solomon et al. 2010).”

“The lateral septum inhibits HPA axis stress responses, and the anatomy of the septal region suggests interactions with hypothalamic and brainstem regions projecting to the PVN (Staiger and Nurnberger 1991; Singewald et al. 2011).”

“Stress/GC-induced reductions in PPG mRNA occur within 30 min and are not accompanied by reduced PPG gene transcription, indicating that GC effects are likely mediated by destabilization of existing RNA pools (Zhang et al. 2009).”

“These inputs are predominately excitatory and serve to activate the HPA axis in response to homeostatic imbalance (Ziegler and Herman 2000; Bartanusz et al. 2004).”

“There is electron microscopy and neurochemical evidence for GR localization to neuronal membranes, in particular postsynaptic membranes, supporting an alternative role for the so-called nuclear receptor (Johnson et al. 2005; Komatsuzaki et al. 2005; Wang and Wang 2009; Prager et al. 2010).”

“Acute activation of the plPFC reduces GC secretion after psychogenic stress (Jones et al. 2011) and restraint-activated neurons of the plPFC express GR (Ostrander et al. 2003), suggesting that GC-sensitive neurons are engaged by stressors.”

“GCs localized to the CeA increase CRH mRNA in the CeA, anterolateral BST, and PVN (Shepard et al. 2000, 2003, 2006).”

“In general, PVN afferent neurons are localized to regions known to receive inputs from somatic nociceptors, visceral afferents, and/or humoral sensory pathways (Kiss et al. 1996; Li et al. 1996).”

“Similar to ilPFC, the amygdala provides excitation of HPA axis responses (Roozendaal et al. 1991; Van de Kar et al. 1991; Roozendaal et al. 1992; Feldman et al. 1994; Feldman and Weidenfeld 1998; Shepard et al. 2003), although there is considerable functional differentiation among individual…”

“Stress is also a prominent risk factor for neurological conditions including epilepsy, Parkinson’s disease, Alzheimer’s disease, and chronic pain, suggesting that GCs play a role in the onset and progression of these disorders (Smith et al. 2002; Myers et al. 2007; Sotiropoulos et al. 2008; Kanner 2009; McEwen and Kal…”

“As the majority of lateral septal neurons express GABA as their transmitter, the HPA inhibitory effects of this region are likely mediated by inhibition of excitatory projections to the PVN (Stevens et al. 1987).”

“The MR has a very high affinity for endogenous GCs and regulates circadian secretory rhythms and ultradian pulsatility (de Kloet et al. 1998; de Kloet and Sarabdjitsingh 2008).”

“Stress is also a prominent risk factor for neurological conditions including epilepsy, Parkinson’s disease, Alzheimer’s disease, and chronic pain, suggesting that GCs play a role in the onset and progression of these disorders (Smith et al. 2002; Myers et al. 2007; Sotiropoulos et al. 2008; Kanner 2009; McEwen and Kal…”

“The PVN also receives input from hypothalamic neuropeptide (e.g., CRH, alpha-melanoctye stimulation hormone) and glutamate expressing neurons (Ziegler and Herman 2000; Zhang and Felder 2004; Rinaman 2007; Ulrich-Lai et al. 2011).”

“However, lesions of the BLA dampen HPA axis responses to psychogenic stress (Bhatnagar et al. 2004) while intra-BLA administration of CRH increases GC secretion (Daniels et al. 2004), indicating this area may also provide feedforward regulation of the HPA axis.”

“Cannabinoid receptors are predominately localized in presynaptic terminals, and CB1 antagonism or knockout leads to elevated CRH expression in the PVN and increased plasma ACTH and CORT (Patel et al. 2004; Cota et al. 2007; Ginsberg et al. 2010; Hill and McEwen 2010).”

“Expression of the MR is particularly pronounced in the lateral septum (Grillo et al. 1990), suggesting that this site may be highly sensitive to modulatory effects of low physiological GCs, perhaps as a means to set the tone of this stress-regulatory region.”

“…feedback is supported by the dense expression of GRs in the hippocampus (Reul and de Kloet 1985), as well as functional studies demonstrating diminished feedback efficacy following hippocampal lesions or local GR inactivation (van Haarst et al. 1997; Herman and Mueller 2006; Mueller et al. 2006).”

“…been reported for an inhibitor of the glycine transporter GlyT1 (Depoort ere et al., 2005), and following epigenetic induction of mGlu2 receptors (Nasca et al., 2013), two treatments that might be expected to potentiate glutamatergic transmission at NMDA receptors (Cubelos et al., 2005;…”

“[135].”

“Control of glucocorticoid release is mediated by glucocorticoid feedback at varying levels of the HPA axis, serving to limit prolonged exposure to catabolic actions of glucocorticoids (117).”

“Activation of the stress response occurs either as a consequence of, or in anticipation of, a challenge (Myers et al., 2012b).”

“These feedback processes help to maintain the cortisol concentration within a narrow physiological window and switch off the stress response (Myers et al. 2012; Wynne and Sarkar 2013).”

“…A uthor M anuscript A uthor M anuscript A uthor M anuscript Feedback Control of the HPA Axis Activation of the HPA axis is limited by glucocorticoid negative feedback inhibition at several levels, ranging from peripheral tissues (e.g., fat) to brain (de Kloet and Herman, 2018; Myers et al., 2012).”

“In contrast, HPA excitation is believed to be mediated largely by the amygdala (Shepard et al. 2003; Myers et al. 2012).”

“Briefly, these circuits have been proposed to form a hierarchy for mediating limbic stress integration and regulating HPA axis responses to psychogenic stressors (Herman et al., 2005; Myers et al., 2012).”

“…of the HPA axis through negative feedback mechanisms that involve both mineralocorticoid and glucocorticoid receptors (MR and GR, respectively), acting at multiple target areas, such as the medial prefrontal cortex, the hippocampal formation, the PVN and the anterior pituitary (Myers et al., 2012).”

“, infralimbic cortex) heavily innervate subcortical autonomic sites and may be involved in stress excitation (Herman, 2009; Myers et al., 2012).”

“…addition to exerting multiple effects throughout the periphery, corticosteroids also exert profound effects on several CNS nuclei [reviewed in (220,347)], including (i) activation of the CeA, BNST, PVN (regions which provide innervation to the LC) as well as the LC itself, (ii) the upregulation…”

“…obvious of these homeostatic mechanisms involves negative feedback regulation by glucocorticoids, via stimulating hippocampal, hypothalamic, and pituitary glucocorticoid receptors to inhibit further secretion of ACTH and CRH, thereby terminating the HPA-axis response to stress (Myers et al. 2012).”

“Glucocorticoid effects are mediated by corticosteroid receptors, which act via genomic as well as non-genomic mechanisms to modulate intracellular signaling [12, 13, 14].”

“Thus, these two tissues have been associated with the central and peripheral control of the HPA-axis, respectively (45).”

“Normally, cortisol regulates its own secretion through a negative feedback loop that inhibits the production of CRH and ACTH.(14) However, during pregnancy, the placenta begins to release CRH into the maternal bloodstream and levels reach 1000–10 000 times that of a nonpregnant woman.”

“been proposed to disinhibit stress responding throughGABA-GABA synaptic connections [33,88,142,144].”

“CRH activates the corticotropes of the anterior pituitary to synthesize and release adrenocorticotropic hormone (ACTH) and β-endorphin into the blood stream [62].”

“In contrast, the amygdala provides excitatory inputs to the HPA axis (Myers et al., 2012).”

“Animal studies have demonstrated that limbic brain development and the HPA axis are highly coupled during development (Myers et al., 2012).”

“In addition to negative feedback mediation by the hippocampus, glucocorticoid receptors are also present in the amygdala, PVN, bed nucleus stria terminalis, and prefrontal cortex (De Kloet et al., 1998; Myers et al., 2012).”

“, 2014) but, in contrast to the hippocampal feedback, amygdalar drive promotes hypothalamic CRH secretion (Herman et al., 2016; Myers et al., 2012), mainly mediated by centromedial nuclei (Herman et al.”

“constrain activation of the HPA axis [21].”

“Notably, glucocorticoids provide a negative feedback signal at peripheral (pituitary) and central (hypothalamus, hippocampus, medial prefrontal cortex) targets to constrain excessive activation of this neuroendocrine system (Myers et al., 2012; Herman et al., 2012).”

“The hypothalamus and pituitary respond to HPA–axis hyperactivity (exhaustion) under chronic stress conditions, as prolonged GC production can result in a negative feedback loop and attenuation of HPA stress response, through reduction of CRH and ACTH output exposure [4,5,7,24,25].”

“The resulting activation of these glucocorticoid receptors terminate the stress response and this is thought to largely subserve HPA axis feedback regulation [11].”

“Put differently, most human stress systems in the body are self-regulating, which prohibits them from staying “on” for extended periods of time [37,38].”

“This mechanism seems to be mediated by an interaction between endocannabinoid and glutamatergic systems (Herman et al., 2012; Myers et al., 2012).”

“This results in GC-mediated fast-feedback inhibition of CRH neurons in the PVN and thus inhibition of ACTH and CORT secretion (Dallman, 2005; Evanson et al., 2010; Groeneweg et al., 2011a, 2011b; Myers et al., 2012).”

“However, persistently altered levels of cortisol can have health-threatening effects (for more details see [5, 6]).”

“In contrast, the GR is only extensively occupied at high circulating glucocorticoid levels, and is the major mediator of negative feedback (Myers et al., 2012).”

“In the mPFC, GR activation is involved with glucocorticoid negative feedback, but in the amygdala, it provides feedforward regulation of the HPA axis (Herman et al., 2016; Myers et al., 2012).”

“Based on current evidence, the dlPFC—a key structure within the CEN—appears to be the best-supported target for addressing EF-related effects of stressors.”

“responsiveness and restoration of homeostasis via the glucocorticoidmediated negative feedback [4].”

“Negative feedback regulation by glucocorticoids occurs both rapidly and over a longer time scale affected by previous stress experience (Myers et al., 2012).”

“neural, behavioral, and metabolic aspects of homeostasis (6).”

“…is regulated via different pathways, including indirect projections from the amygdala to the hypothalamic paraventricular nucleus (Herman, et al., 2003; Myers, et al., 2012) and other alternative pathways that could differently impact the HPA axis reactivity in the absence of a functional amygdala.”

“…in neural activation and/or mRNA expression of stress neuropeptides in limbic-forebrain regions that are involved in HPA regulation (Herman et al., 2005; Myers et al., 2012)—the medial prefrontal cortex (mPFC), amygdala, hippocampus and hypothalamus (Raineki et al., 2014; Lan et al., 2015).”

“…as a relay station between limbic processing of emotional information and elaboration of physiological and behavioral responses to stress (Adhikari, 2014; Choi et al., 2007; M AN US CR IP T AC CE PT ED ACCEPTED MANUSCRIPT 13 Crestani et al., 2013; Myers et al., 2012; Ulrich-Lai and Herman, 2009).”

“, 2008), with GR being of particular importance in mediating glucocorticoid feedback inhibition of the HPA axis (Myers et al., 2012).”

“, 2012 [77] for a review of feedback mechanisms).”

“In both, CORT translocates to the nucleus coupled to a GR and inhibit the transcription of CRH and ACTH genes, decreasing the signal to continue the stress response.”

“This response is regulated by negative and positive feedback mechanisms, where glucocorticoids (GCs) released from the adrenal gland can inhibit or stimulate (respectively) their own genomic and non-genomic actions by binding to glucocorticoid receptors (GRs) in the brain [7,8].”

“These changes in glucocorticoid-metabolizing enzymes and receptor genes indicate an enhanced negative feedback regulation of the HPA axis to control and maintain glucocorticoid homeostasis (Myers et al., 2012).”

“For example, glucocorticoids have been found to exert a direct, inhibitory influence on the activity of the hypothalamic–pituitary–adrenal (HPA) axis at the level of the central nervous system (Myers et al., 2012; Tasker et al., 2011).”

“Activation of GR in the amygdala, including the central nuclei, has been implicated in mediating the positive feedback loop that potentiates the activity of the HPA axis (Myers et al., 2012).”

“In this regard, glucocorticoids act as potent negative regulators of the HPA axis activity: by binding to their receptors in different structures, glucocorticoids extinguish the HPA axis response [39,41].”

“When these circuits trigger autonomic and endocrine stress responses, brainstem centres as well as the hypothalamic-pituitary-adrenal (HPA) are activated 8,9,13 .”