Psychotherapy and Neuroscience

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.


American Psychiatric Association. (1994): Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. American Psychiatric Association, Washington D.C.

Anagnostaras SG, Gale GD, Fanselow MS (2001): Hippocampus and contextual fear conditioning: recent controversies and advances. Hippocampus, 11910: 8-17.

Bremner JD, Narayan M, Anderson ER, Staib LH, Miller HL, Charney DS (2000): Hippocampal volume reduction in major depression. Am J Psychiatry, 157(1): 115-8.

Bremner JD, Randall P, Vermetten E, Staib L, Bronen RA, Mazure C, Capelli S, ScCarthy G, Innis RB, Charney DS (1997): Magnetic resonance imaging-based measurement of hippocampal volume in posttraumatic stress disorder related to childhood physical and sexual abuse-a preliminary report. Biol Psychiatry, 41(1): 23-32.

Bremner JD, Vythilingam M, Vermetten E, Southwick SM, McGlashan T, Nazeer A, Khan S, Vaccarino LV, Soufer R, Garg PK, Ng CK, Staib LH, Duncan JS, Charney DS (2003): MRI and PET study of deficits in hippocampal structure and function in women with childhood sexual abuse and posttraumatic stress disorder. Am J Psychiatry, 160(5): 924-32.

Bucci DJ, Phillips RG, Burwell RD (2000): Contributions of postrhinal and perirhinal cortex to contextual information processing. Behav Neurosci, 114(5): 882-94.

Bucci DJ, Saddoris MP, Burwell RD (2002): Contextual fear discrimination is impaired by damage to the postrhinal or perirhinal cortex. Behav Neurosci, 116(3): 479-88.

Campeau S, Davis M (1995): Involvement of subcortical and cortical afferents to the lateral nucleus of the amygdala in fear conditioning measured with fear-potentiated startle in rats trained concurrently with auditory and visual conditioning stimuli. J Neurosci, 15(3): 2312-27.

Cole MA, Kalman BA, Pace TW, Topczewski F, Lowrey MJ, Spencer RL (2000): Selective blockade of the mineralocorticoid receptor impairs hypothalamic-pituitary-adrenal axis expression of habituation. J Neuroendocrinol, 12(10): 1034-42.

Davachi L, Wagner AD (2002): Hippocampal contributions to episodic encoding: insights from relational and item-based learning. J Neurophysiol, 88(2): 982-90.

De Kloet ER, Reul JM (1987): Feedback action and tonic influence of corticosteroids on brain function: a concept arising from the heterogeneity of brain receptor systems. Psychoneuroendocrinology, 12: 83-105.

De Kloet ER, Oitzl MS, Joels M (1993): Functional implications of brain corticosteroid receptor diversity. Cell Mol Neurobiol, 13(4): 433-55.

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, Oitzl MS, Joels M (1999): Stress and cognition: are corticosteroids good or bad guys? Trends Neurosci, 22(10): 422-6.

Deak T, Nguyen KT, Cotter CS, Fleshner M, Watkins LR, Maier SF, Spencer RL (1999): Long-term changes in mineralcorticoid and glucocorticoid receptor occupancy following exposure to an acute stressor. Brain Res, 847(2): 211-20.

Debiec J, LeDoux JE, Nader K (2002): Cellular and systems reconsolidation in the hippocampus. Neuron, 36(3): 527-38.

Duzel E, Vargha-Khadem F, Heinze HJ, Mishkin M (2001): Brain activity evidence for recognition without recollection after early hippocampal damage. Proc Natl Acad Sci U S A, 98(14): 8101-6.

Fortin NJ, Agster KL, Eichenbaum HB (2002): Critical role of the hippocampus in memory for sequences of events. Nat Neurosci, 5(5): 458-62.

Fries P, Fernandez G, Jensen O (2003): When neurons form memories. Trends Neurosci, 26(3): 123-24.

Heim C, Ehlert U, Hellhammer DH (2000): The potential role of hypocortisolism in the pathophysiology of stress-related bodily disorders. Psychoneuroendocrinology, 25(1): 1-35.

Herman JP, Schafer MK, Young EA, Thompson R, Douglass J, Akil H, Watson SJ (1989): Evidence for hippocampal regulation of neuroendocrine neurons of the hypothalamo-pituitary-adrenocortical axis. J Neurosci, 9(9): 3072-82.

Herman JP, Cullinan WE, Morano MI, Akil H, Watson SJ (1995): Contribution of the ventral subiculum to inhibitory regulation of the hypothalamo-pituitary-adrenocortical axis. J Neuroendocrinol, 7(6): 475-82.

Herman JP, Dolgas CM, Carlson SL (1998): Ventral subiculum regulates hypothalamo-pituitary-adrenocortical and behavioral responses to cognitive stressors. Neuroscience, 86(2): 449-59.

Herman JP, Spencer R (1998): Regulation of hippocampal glucocorticoid receptor gene transcription and protein expression in vivo. J Neurosci, 18(18): 7462-73.

Herr AS, Tsolakidou AF, Yassouridis A, Holsboer F, Rein T (2003): Antidepressants differentially influence the transcriptional activity of the glucocorticoid receptor in vitro. Neuroendocrinology, 78(1): 12-22.

Heuser I, Deuschle M, Weber B, Stalla GK, Holsboer F (2000): Increased activity of the hypothalamus-pituitary-adrenal system after treatment with the mineralcorticoid receptor antagonist spironolactone. Psychoneuroendocrinology, 25(5): 513-8.

Hock BJ Jr, Bunsey MD (1998): Differential effects of dorsal and ventral hippocampla lesions. J Neurosci, 18(17): 7027-32.

Hoffman KL, McNaughton BL (2002): Coordinated reactivation of distributed memory traces in primate neocortex. Science, 297(5589): 2070-3.

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

Kjelstrup KG, Tuvnes FA, Steffenach HA, Murison R, Moser EI, Moser MB (2002): Reduced fear expression after lesions of the ventral hippocampus. Proc Natl Acad Sci U S A, 99(16): 10825-30.

Kudrimoti HS, Barnes CA, McNaughton BL (1999): Reactivation of hippocampal cell assemblies: effects of behavioral state, experience, and EEG dynamics. J Neurosci, 19(10): 4090-101.

Louie K, Wilson MA (2001): Temporally structured replay of awake hippocampal ensemble activity during rapid eye movement sleep. Neuron, 29(1): 145-56.

MacQueen GM, Campbell S, McEwen BS, Macdonald K, Amano S, Joffe RT, Nahmias C, Young LT (2003): Course of illness, hippocampal function, and hippocampal volume in major depression. Proc Natl Acad Sci U S A, 100(3): 1387-92.

Malberg JE, Eisch AJ, Nestler EJ, Duman RS (2000): Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. J Neurosci, 20(24): 9104-10.

Mallei A, Shi B, Mocchetti I (2002): Antidepressant treatments induce the expression of basic fibroblast growth factor in cortical and hippocampal neurons. Mol Pharmacol, 61(5): 1017-24.

Maren S, Fanselow MS (1997): Electrolytic lesions of the fimbria/fornix, dorsal hippocampus, or entorhinal cortex produce anterograde deficits in contextual fear conditioning in rats. Neurobiol Learn Mem, 67(2): 142-9.

McNish KA, Gewirtz JC, Davis M (1997): Evidence of contextual fear after lesions of the hippocampus: a disruption of freezing but not fear-potentiated startle. J Neurosci, 17(2): 9353-60.

Messinger A, Squire LR, Zola SM, Albright TD (2001): Neuronal representations of stimulus associations develop in the temporal lobe during learning. Proc Natl Acad Sci U S A, 98(21): 12239-44.

Mishkin M, Suzuki WA, Gadian DG, Vargha-Khadem F (1997): Hierarchical organization of cognitive memory. Philos Trans R Soc Lond B Biol Sci, 352(1360): 1461-7.

Mishkin M, Vargha-Khadem F, Gadian DG (1998): Amnesia and the organization of the hippocampal system. Hippocampus, 8(3): 212-6.

Nettles KW, Pesold C, Goldman MB (2000): Influence of the ventral hippocampal formation on plasma vasopressin, hypothalamic-pituitary-adrenal axis, and behavioral responses to novel acoustic stress. Brain Res, 858(1): 181-90.

Okugawa O, Suzukawa F, Toshihilo K, Inagaki C (1999): Long-term treatment with antidepressants increases glucocorticoid receptor binding and gene expression in cultured rat hippocampal neurones. J Neuroendocrinol, 11(11): 887-95.

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): Glucocorticoid receptors in major depression: relevance to pathophysiology and treatment. Biol Psychiatry, 49(5): 391-104.

Phillips RG, LeDoux JE (1992): Differential contribution of amygdala and hippocampus to cued and contextual fear conditioning. Behav Neurosci, 106(2): 274-85.

Phillips RG, LeDoux JE (1994): Lesions of the dorsal hippocampal formation interfere with background but not foreground contextual fear conditioning. Learn Mem, 1(1): 34-44.

Quinn JJ, Oommen SS, Morrison GE, Fanselow MS (2002): Post-training excitotoxic lesions of the dorsal hippocampus attenuate forward trace, backward trace and delay fear conditioning in a temporally specific manner. Hippocampus, 12(4): 495-504.

Reul JM, Stec I, Soder M, Holsboer F (1993): Chronic treatment of rats with the antidepressant amitriptyline attenuates the activity of the hypothalamic-pituitary-adrenocortical system. Endocrinology, 133(1): 312-20.

Richmond MA, Pouzet B, Veenman L, Feldon J, Yee BK, Rawlins JN, Bannerman DM (1999): Dissociating context and space within the hippocampus: effects of complete, dorsal, and ventral excitotoxic hippocampal lesions on conditioned freezing and spatial learning. Behav Neurosci, 113(6): 1189-1203.

Rudy JW, Barrientos RM, O’Reilly RC (2002): Hippocampal formation supports conditioning to memory of a context. Behav Neurosci, 116(4): 530-8.

Santarelli L, Saxe M, Gross C, Surget A, Battaglia F, Dulawa S, Weisstraub N, Lee J, Duman R, Arancio O, Belzung C, Hen R (2003): Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science, 301(5634): 805-9.

Shastri L (2002): Episodic memory and cortico-hippocampal interactions. Trends Cogn Sci, 6(4): 162-8.

Sheline YI, Gado MH, Kraemer HC (2003): Untreated depression and hippocampal volume loss. Am J Psychiatry, 160(8): 1516-8.

Spencer RL, Kim PJ, Kalman BA, Cole MA (1998): Evidence for mineralocorticoid receptor facilitation of glucocorticoid receptor-dependent regulation of hypothalamic-pituitary-adrenal axis activity. Endocrinology, 139(6): 2718-26.

Stein MB, Koverola C, Hanna C, Torchia MG, McClarty B (1997): Hippocampal volume in women victimized by childhood sexual abuse. Psychol Med, 27(4): 951-9.

Stickgold R, Hobson JA, Fosse R, Fosse M (2001): Sleep, learning, and dreams: off-line memory reprocessing. Science, 294(5544): 1052-7.

Sutherland GR, McNaughton B (2000): Memory trace reactivation in hippocampal and neocortical neuronal ensembles. Curr Opin Neurobiol, 10(2): 180-6.

Tassoni G, Lorenzini CA, Baldi E, Sacchetti B, Bucherelli C (1999): A peculiar pattern of temporal involvement of rat perirhinal cortex in memory processing. Behav Neurosci, 113(6): 1161-9.

Van der Kolk BA (1996): The complexity of adaptation to trauma: self-regulation, stimulus discrimination, and characterological development. In: Traumatic Stress: The Effects of Overwhelming Experience on Mind, Body, and Society. Eds. BA van der Kolk, AC McFarlane, L Weisaeth, pp.182-213, Guilford Press, New York.

Vermetten E, Vythilingam M, Southwick SM, Charney DS, Bremner JD (2003): Long-term treatment with paroxetine increases verbal declarative memory and hippocampal volume in posttraumatic stress disorder. Biol Psychiatry, 54(7): 54(7): 693-702.

Villarreal G, Hamilton DA, Petropoulos H, Driscoll I, Rowland LM, Griego JA, Kodituwakku PW, Hart BL, Escalona R, Brooks WM (2002): Reduced hippocampal volume and total white matter volume in posttraumatic stress disorder. Biol Psychiatry, 50(2): 119-25.

Vythilingam M, Heim C, Newport J, Miller AH, Anderson E, Bronen R, Brummer M, Staib L, Vermetten E, Charney DS, Nemeroff CB, Bremner JD (2002): Childhood trauma associated with smaller hippocampal volume in women with major depression. Am J Psychiatry, 159(12): 2072-80.

Wirth S, Yanike M, Frank LM, Smith AC, Brown EN, Suzuki WA (2003): Single neurons in the monkey hippocampus and learning of new associations. Science, 300(5625): 1578-81.

Young EA, Lopez JF, Murphy-Weinberg V, Watson SJ, Akil H (1998): The role of mineralocorticoid receptors in hypothalamic-pituitary-adrenal axis regulation in humans. J Clin Endocrinol Metab, 83(9): 3339-45.