Neurohormones & HPA

Normally when a stimulus is perceived as stressful, e.g. external or internal cues of threat, pain, or failure of expectation (Ladd et al., 2000), corticotropin releasing hormone (CRH) neural activity in the amygdala provides input to the locus coeruleus to stimulate noradrenergic neurons for sympathetic nervous system (SNS) activity (Melia & Duman, 1991) and the medial parvocellular region of the paraventricular nucleus (mPVNpc) of the hypothalamus for hypothalamic-pituitary-adrenal axis (HPA axis) activity (Heim & Nemeroff, 1999). As the synthesis of PVN CRH increases, CRH and arginine-vasopressin (AVP) are both released from the terminals in the median eminence into the hypothalamic hypophysial portal vascular system that connects the hypothalamus with the pituitary gland (Plotsky, 1991; Tsigos & Chrousos, 2003). CRH in the anterior pituitary facilitates the release of the analgesic pro-opiomelanocortin (POMC) gene expression and the release of two POMC-derived peptides, adrenocorticotropin hormone (ACTH) and β-endorphin (Arborelius et al., 1999). AVP as a co-secretatogue with CRH also stimulates ACTH secretion (Tsigos & Chrousos, 2003). ACTH induces the synthesis and release of glucocorticoids (GCs) in the adrenal cortex. GCs are the end products of the HPA axis (Ladd et al., 2000), sources of negative feedback inhibition to regulate HPA activity, and regulators of stress arousal (Sapolsky et al., 1990; Jacobson & Sapolsky, 1991). Central GC injection acting on PVN GRs downregulates CRH mRNA and inhibits medial parvocellular (mPVNpc) neurons (CRH and AVP) and in response to neural activity in the mPVNpc indirectly decreases ACTH secretion in the anterior pituitary (Makino et al., 1994; Herman & Cullinan, 1997).

Glucocorticoids (GCs), i.e. cortisol in primates and corticosterone in rats, are endogenous steroids (corticosteroids) that normally occupy or bind to glucocorticoid receptors (GRs) throughout the brain and central (CNS) nervous system. According to the “nucleocytoplasmic traffic model” of GR action, the GR in absence of ligand and in its “unactivated” form, resides primarily in the neuron’s cytoplasm in association with several heat shock and other proteins to form the cytoplasmic chaperon protein complex (Miller & Pariante, 2001). In response to ligand binding the protein complex dissociates from the cytoplasm and with the receptor’s continued association with the heat shock (e.g. hsp90) and other proteins translocates to the nucleus by tracking along the cytoskeleton to the nuclear pore (Galigniana et al., 1998; Hache et al., 1999; Pratt et al., 1999). Once in the nucleus the receptor dimerizes and binds to specific response elements called hormone or glucocorticoid responsive elements (HRE or GRE) or “dimers” that allow DNA to bind to the receptor (de Kloet et al., 1998; O’Connor et al., 2000). As the ligand-bound receptor dimerizes and binds to DNA responsive GREs, it stimulates receptor gene transcription (de Kloet et al., 1998; Owen, 2002). GRs along with activating protein (AP-I) and nuclear factor κB (NFκB) interact with other transcription factors, i.e. to attenuate stress-induced signals through the receptor’s membrane (de Kloet, 2003). Activated GRs also have the capacity to block other transcription factors from binding to their own transcription elements, such as those for certain proinflammatory cytokines (e.g. IL-1β and TNF-γ) and corticotropin releasing hormone (CRH) by direct protein to protein interaction (O’Connor et al., 2000). This process or transrepression (Meijer, 2002) inhibits other transcription factors from transcribing and this results in their receptor downregulation and instability in their messenger RNA (Chrousos, 1995; Tsigos & Chrousos, 2003).

Typically the circulating steroid binds to its receptor and this initiates the process of gene transcription. Reduced GR levels, binding, and reduced gene transcription in the affective disorder depression may be due to either GR failure to associate with chaperon proteins due to chronic levels of the circulating steroid (Pariante & Miller, 2001) or mutations in the GR DBD that impairs DNA binding serving to decrease ligand nuclear occupancy (Hache et al., 1999). As GRs downregulate, their binding of ligand decreases, circulating steroid levels increase, and structures that are dependent on the steroid to maintain their functional integrity are deprived of it. Thus, moderate amounts of circulating steroid can bind to receptors to enhance receptor functional integrity; however, high levels of circulating GCs seem to interfere in GR transcription. As noted in future sections of this web site the most common manifestation of an organism’s response to stress is circulating steroid, GCs, corticosterone, cortisol, etc. in the plasma, cerebrospinal fluid, saliva, and urine.

Interestingly, at therapeutic levels both tricyclic and bicyclic antidepressants in the steroid’s presence in vitro induce GR translocation from the cytoplasm to the nucleus and mediate gene transcription (Pariante et al., 1997, 2001) that allows for increased steroid binding to the receptor. Antidepressants in this context mediate transcription factors that allow for GR gene transcription. This facilitates the functional integrity of the glucocorticoid receptor. As a result of gene transcription the receptor and the respective neuron, in which it is housed, is better able to contain and express ligand and reduce ligand transport as it approaches and travels across the neuron’s synapse respectively. An antidepressant therapy’s efficacy is usually assessed within the context of decreased pre or post-synaptic ligand transport and increased reuptake at the synaptic level. It is actually the full functional genetic expression of the receptor that inhibits ligand synaptic transport. Antidepressant therapy also increases GR (Okugawa et al., 1999) and mineralocorticoid receptor (MR) binding in the hippocampus (Reul et al., 1993) and this decreases or inhibits HPA-related stress arousal (Deuschle et al., 2003). Section 1.42 will elaborate on how functional hippocampal GRs actively inhibit HPA activity (Jacobson & Sapolsky, 1991) and are the first line of defense to inhibit stress-induced HPA activity. Maintaining the functional integrity of both the mineralocorticoid and glucocorticoid receptor is essential for sustaining necessary negative feedback over HPA activity.

References

Arborelius L, Owens MJ, Plotsky PM, Nemeroff CB (1999): The role of corticotropin-releasing factor in depression and anxiety disorders. J Endocrinol, 160(1): 1-12.

Chrousos GP (1995): The hypothalamic-pituitary-adrenal axis and immune-mediated inflammation. N Engl J Med, 332(20): 1351-62.

De Kloet ER, Vreugdenhil E, Oitzl MS, Joels M (1998): Brain corticosteroid receptor balance in health and disease. Endocr Rev, 19(3): 269-301.

De Kloet ER (2003): Hormones, brain, and stress. Endocr Regul, 37(2): 51-68.

Deuschle M, Hamann B, Meichel C, Krumm B, Lederbogen F, Kniest A, Colla M, Heuser I (2003): Antidepressive treatment with amitriptyline and paroxetine: effects on saliva cortisol concentrations. J Clin Psychopharmacology, 23(2): 201-5.

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Hache RJ, Savory JG, Lefebvre (1999): Nucleocytoplasmic trafficking and glucocorticoid receptor function. Gene Ther Mol Biol, 4: 99-107.

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Herman JP, Cullinan WE (1997): Neurocircuitry of stress: central control of the hypothalamo-pituitary-adrenocortical axis. Trends Neurosci, 20(2): 78-84.

Jacobson L, Sapolsky R (1991): The role of the hippocampus in feedback regulation of the hypothalamic-pituitary-adrenocorticortical axis. Endocr Rev, 12(2): 118-34.

Ladd CO, Huot RL, Thrivikraman KV, Nemeroff CB, Meaney MJ, Plotsky PM (2000): Long-term behavioral and neuroendocrine adaptation to adverse experience. Prog Brain Res, 122: 81-103.

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Meijer OC (2002): Coregulator proteins and corticosteroid action in the brain. J Neuroendocrinol, 14(6): 499-505.

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Pariante CM, Pearce BD, Pisell TL, Owens MJ, Miller AH (1997): Steroid-independent translocation of the glucocorticoid receptor by the antidepressant desipramine. Mol Pharmacol, 52(4): 571-81.

Pariante CM, Makoff A, Lovestone S, Feroli S, Heyden A, Miller AH, Kerwin RW (2001): Antidepressants enhance glucocorticoid receptor function in vitro by modulating the membrane steroid transporters. Br J Pharmacol, 134(6): 1335-43.

Pariante CM, Miller AH (2001): Glucocoricoid receptors in major depression: relevance to pathophysiology and treatment. Biol Psychiatry, 49(5): 391-104.

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Pratt WB, Silverstein AM, Galigniana MD (1999): A model for the cytoplasmic trafficking of signalling proteins involving the hsp90-binding immunophilins and p50cdc37cdc37. Cell Signal, 11(12): 839-51.

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Tsigos C, Chrousos GP (2003): Hypothalamic-pituitary-adrenal axis, neuroendocrine factors and stress. J Psychosom Res, 53(4): 865-71.

HPA Inhibition

The hippocampus is a limbic structure that is located in the medial temporal lobe (MTL) along with the subhippocampal area (composed of the entorhinal, perirhinal, and parahippocampal cortices). Removal of the hippocampal and subhippocampal areas impairs the spontaneous retrieval of context rich episodic memory that involves cohesive sequencing of events and their recognition (Mishkin et al., 1997, 1998; Duzel et al., 2001; Davachi & Wagner, 2002; Fortin et al., 2002), respectively. The hippocampal region develops episodic and new associative memory by encoding initial (Sutherland & McNaughton, 2000) and intermediate (Fries et al., 2003) memory traces that reflect that learning before, during and after an event or training has taken place (Wirth et al., 2003). Laying down temporal sequences of episodic memory traces (Shastri, 2002) as such mediates memory reconstruction for the serial recreation of the original event, which will later allow for full recall of an event or a series of episodes. Memory trace formation and consolidation are two processes that comprise and underlie memory reconstruction for future recall.

EEG theta activity enhances learning-associated long-term potentiation (LTP) and initial informational transfer from the neocortex to the hippocampal formation (Stickgold et al., 2001). Subsequent memory consolidation that involves hippocampal neural encoding to the sensory and prefrontal cortices (Messinger et al., 2001) ensures that memories will eventually become independent of the hippocampal region over time (Sutherland & McNaughton, 2000; Fries et al., 2003). As evidenced in patterns of neural activity in electrophysiological studies in the course of consolidation the hippocampal region also needs to replay post-training neural information for the processing of procedural or episodic memory, in temporal and serial sequence (Kudrimoti et al., 1999; Louie & Wilson, 2001). Reenactment of neural activity during post-training rest periods is necessary to reactivate patterns and preserve the temporal order of neuronal activation (Hoffman & McNaughton, 2002; Fries et al., 2003). Replay and reenactment not only help to form memory traces but also bring to mind fine details that had not been thought about during the event or training and also the formation of new associations. In summary, replay and reenactment facilitate the encoding of memory traces relating to various temporal sequences to aid in memory consolidation and reconstruction that underlies the ability for future recall. With each successful recall, an event’s episodic memory trace becomes activated and strengthened and is reinstated within cortical circuitry (Shastri, 2002).

Removal of the hippocampus proper (Phillips & LeDoux, 1992), impairs contextual fear conditioning. Lesioning of its dorsal region (Phillips & LeDoux, 1994; Maren & Fanselow, 1997; Anagnostaras et al., 2001; Rudy et al., 2002) produces impairments in identifying environmental sensory components relating to location that have been associated with specific fear producing cues or stimuli. Removal of hippocampal ventral portions (Hock & Bunsey, 1998; Richmond et al., 1999; Kjelstrup et al., 2002) produces impairments in the ability to form associations between fear induced internal states of arousal and fear-inducing conditioned cues. These deficits probably emanate from deficits in retrieval as post-training lesions of the hippocampus (McNish et al., 1997; Quinn et al., 2002) or surrounding subhippocampal regions (Campeau & Davis, 1995; Bucci et al., 2000, 2002) impair recognition of fear producing contexts. Impairments in conditioning have been noted as late as post-training days 15 and 45 in response to infusion of protein synthesis inhibitor anisomycin (Debiec et al., 2002). The delay in post-training response is suggestive of the hippocampal region’s involvement in later memory consolidation and lack of involvement during earlier consolidation periods (Tassoni et al., 1999). The recall for significant events seems to require hippocampal involvement through its consolidation function. Interpretation of fear conditioning within the context of hippocampal lamina distribution will be provided in much greater detail in section 3.0 of this web site.

Hippocampal input onto entorhinal cortical layer V (Mallei et al., 2002) is critical for providing regulatory tone and reactive inhibition of HPA activity. Stimulation of the hippocampus decreases HPA activity in both rats and humans (Jacobson & Sapolsky, 1991). Removal of the hippocampus and the surrounding area increases PVN CRH mRNA levels in response to stress (Herman et al., 1989). As noted in section 1.41increased synthesis and release of CRH is associated with the onset of HPA activity and the stress neurohormone cascade. More restricted neurotoxin lesions of the ventral subiculum and ventral cornu ammonis CA1 (with limited CA3 and dentate gyrus involvement) leads to increased plasma corticosterone levels in response to sixty minutes of stress (Herman et al., 1995). Those limited to the ventral subiculum lead to a robust enhancement of HPA responses to chronic restraint stress, as evidenced in increased corticosterone secretion (Herman et al., 1998) and increased fear and stress-related behaviors of startle, freezing, and flight/escape (Nettles et al., 2000). Functionally intact hippocampal regions, CA1 and ventral subiculum, are needed to facilitate regulatory tone over HPA activity.

Hippocampal mineralocorticoid receptors (MRs) and glucocorticoid receptors (GRs) are the first line of defense to inhibit the hypothalamic-pituitary-adrenal axis (HPA) activity. MRs are involved in corticosterone-related maintenance of basal HPA response and daily circadian variations of corticosterone and in appraisal of information and response selection. In addition hippocampal MR activity regulates HPA excitatory output by exerting GABAergic inhibitory tone on paraventricular nucleus of the hypothalamus (PVN) neurons (de Kloet et al., 1998; Young et al., 1998). Furthermore MR activation is essential for mediating and maintaining selective attention, appraisal and interpretation of environmental contingencies, behavioral response selection, and the stabilization of excitability by habituation processes (de Kloet et al., 1993, 1998, 1999; Cole et al., 2000; Heuser et al., 2000). MR expression mediates the proactive avoidance of environmentally stressful situations, approach towards rewarding situations, and overall maintenance of adaptive homeostasis.

Hippocampal GR functional integrity depends on MR mediated diurnal levels to facilitate homeostasis and daily stress recovery (de Kloet et al., 1998; Spencer et al., 1998). GR expression in coordination with MRs mediates steroid control of stress recovery by providing reactive feedback and suppressing excitability (de Kloet & Reul, 1987). Repeated GR activation in response to multiple chronic task-related stressors disrupts the function of MRs during the retrieval process (de Kloet et al., 1999). Reductions in MR mRNA enhance GR mRNA in the hippocampal CA1 and dentate gyrus regions in vivo (Herman & Spencer, 1998) and response inhibition and negative feedback on HPA activity (de Kloet & Reul, 1987). Hippocampal GR activation also disinhibits MR-mediated suppression on HPA activity and facilitates hippocampal disinhibition over PVN GRs and their expression (de Kloet et al., 1993). Chronic multiple stressors (such as immobilization, isolation, crowding, forced swim, etc.) induce cumulative PVN GR mRNA decreases that allow for CRH mRNA. PVN CRH expression initiates adrenocortical negative feedback (Herman et al., 1995) over HPA activity and associated GC secretion (Deak et al., 1999) as noted in section 1.41. Hippocampal GRs also promote processes underlying the consolidation of acquired information to make memory amenable for later recall (de Kloet et al., 1999).

Because both hyperactivation and hypoactivation of MRs and GRs can impair both the functional integrity of receptors and long term potentiation (LTP) in respective neurons, de Kloet and colleagues (1998) hypothesized that psychiatric conditions like post-traumatic stress disorder (PTSD) and major depression might be characterized by hyper and hypoactivation of hippocampal MRs and GRs respectively. This is in part substantiated clinically, as patients with PTSD selectively attend away from processing traumatic material and experience behavioral avoidance of traumatic triggers and generalized hyperarousal. This is probably reflective of MR hyperactivation. Patients with PTSD also experience intrusive memories (i.e. reexperiencing terror-filled sensory memory relating to a prior traumatic experience in the present), abreaction (i.e. unknowingly reliving terror-filled sensory memory relating to a prior traumatic experience in the present), and panic attacks (i.e. terror-filled emotion that emanates from prior traumatic experience) (American Psychiatric Association, 1994). The condition is also characterized by compulsions to repeat trauma by compulsively and unwittingly reliving trauma in setting up future scripts for revictimization or victimizing others (van de Kolk, 1996). Intrusive memories, abreactions, and reliving traumatic scripts may be reflective of GR of consolidation-related reexperiencing, reliving, and reenacting activity noted above. These symptoms are probably unconscious attempts at memory processing and consolidation. Furthermore PTSD is a condition that is also associated with hypoactive HPA activity (Heim et al., 2000). Major depression on the other hand is a condition that is characterized by hyperactive HPA and increased synthesis and release of cortisol or hypercortisolism (Pariante & Miller, 2001). Due to the condition’s reliance on HPA activity for negative feedback, it is possible that hippocampal MRs and GRs are hypoactive.

The loss of hippocampal functional integrity may be reflected as reduced hippocampal volume in magnetic resonance imaging (MRI) findings. In fact untreated patient populations, i.e. patients having PTSD symptoms (Bremner et al., 1997; Stein et al., 1997; Villarreal et al., 2002; Bremner et al., 2003) and major depression (Bremner et al., 2000; Vythilingam et al., 2002; MacQueen et al., 2003; Shiline et al., 2003), both demonstrate reduced MRI hippocampal volumes when compared with normal controls. Interestingly antidepressant therapy with paroxetine (Vermetten et al., 2003) increases hippocampal volume in patient populations with PTSD according to MRI findings. Increases in hippocampal volume are probably reflective of increased neurogenesis in this region (Malberg et al., 2000; Santarelli et al., 2003). This is mediated by the 5-HT1A’s agonist’s permissive role in increasing GR gene transcription in response to circulating steroid (Parente et al., 1997, 2001; Herr et al., 2003) and increased hippocampal GR binding (Reul et al., 1993; Okugawa et al., 1999). Antidepressant therapy probably slows PTSD hyperactive hippocampal GRs (to increase receptor binding) to regulate hyperactive memory consolidation processes, reducing consolidation-related symptoms of intrusive memories or abreaction. On the other hand antidepressant therapy for major depression may work to increase the functional integrity of hippocampal MRs, by increasing MR binding (Reul et al., 1993). This synergistically activates hypoactive MRs to improve their function for inhibitory tone over HPA activity (as noted above) and also allows GRs to improve their inhibitory role in stress reactivity.

In summary, the hippocampus provides the first line of defense to regulate HPA arousal through activation of hippocampal MRs for basal inhibitory tone and then GRs for stress reactivity. Receptor hyper or hypoactivation in response to multiple and chronic stressors effects the functional integrity of these receptors. Stress over time impairs their function and results on an over reliance on the HPA and other central hormonal systems for negative feedback to facilitate stress-arousal inhibition. The following sections will examine patient populations and the nature of their responses to stress at hypothalamic-pituitary-adrenal cortex levels. References to the inhibitory role of the hippocampus and steroid receptors will be inserted as needed to enhance discussion.

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