Overall Goals

This project focuses upon interactions between the amygdala and hippocampus with respect to stressand fear-related learning and has collaborations with Project 1 on fear conditioning and with Project 3 regarding exciatory amino acid receptors. Project 4 includes a component to study changes in human dentate gyrus vs. Ammon's horn volume that relates to clinical work in Projects 1 and 2 and will be supported by the Quantitative Morphometry Core (QMC) under the direction of Dr. Patrick Hof at Mt. Sinai.

The hippocampus is an important part of limbic circuits subserving anxiety and fear; and hippocampal malfunction may contribute to cognitive impairment in anxiety disorders 45,89. Hippocampal function is strongly implicated in contextual fear conditioning 67,80 and in passive avoidance learning 85 and the dentate gyrus is dependent on normal projections from the amygdala for displaying long-term potentiation, LTP 50,51,54. Moreover, psychological stress causes the hippocampus to undergo a number of changes in structure and function: acute psychosocial stress inhibits neurogenesis in tree shrews and marmosets 40,42, and chronic stress has an even larger effect on neurogenesis and reduces dentate gyrus volume in the tree shrew 32; chronic psychological stress causes remodelling (atrophy) of apical dendrites of CA3 pyramidal neurons that receive mossy fiber input from DG granule neurons 61,62,69,71 and also causes mossy fiber terminals to become depleted of synaptic vesicles 63.

Chronic restraint stress also increases fear responding in an open field and to both tone and context conditioning 20. These effects, which emphasize that repeated psychological stress can markedly enhance fear responses, are independent of hippocampal CA3 neuronal atrophy and related spatial learning impairment. Moreover, more subtle influences of hippocampal structural alterations on fear conditioning based upon context discrimination will be investigated in Proj.1 to form the basis for further studies of hippocampal and stress involvement in fear learning.

The human hippocampus is reported to undergo atrophy in a number of conditions related to stress and/or elevated glucocorticoids: recurrent depressive illness, post-traumatic stress disorder (PTSD), Cushing's syndrome and mild cognitive impairment during aging 12,21,38,46,88,95. However, it is not yet known whether this atrophy is the product of dentate gyrus shrinkage, Ammon's horn atrophy, or both. Neurogenesis, suppressible by stress, occurs in the adult new and old world primate brain, as well as in rats and tree shrews, a primitive primate species, as noted above (33,40,42; Gould, personal communication).

We propose that changes in neurogenesis and granule neuron survival in the dentate gyrus, resulting in altered size and altered circuitry, are likely to influence the function of the limbic brain circuits that are implicated in symptoms of a variety of psychiatric illnesses, particularly since the dentate gyrus (DG) is intimately associated with the entorhinal cortex (EC), which is functionally linked to the amygdala and medial prefrontal cortex (mPFC) and also is influenced by the basolateral amygdala. Among other questions, Project 4 addresses the possible role of neuronal turnover in the dentate gyrus in the formation and extinction of fear-related memories and it examines the interaction between chronic stress and acute fear conditioning on neurogenesis and dentate gyrus volume and neuron number; it also deals directly with the issue of translation between studies on human brain morphology and animal brain morphology. Project 4 is built around a central hypothesis that lead to a number of research questions and reflects extensive collaborations with Proj. 1, 2 and 3.


Research Plan

Central Hypothesis: Stressors facilitate mechanisms subserving fear in the amygdala and inhibit neurogenesis in granule neurons of the dentate gyrus both acutely and chronically; and, in part by enhancing amygdala output, chronic stress results in decreased dentate gyrus volume and altered connectivity and function that impairs the ability of the hippocampus to participate in context-dependent fear.

Specific Aims:

1. To compare amygdala and DG long-term potentiation and study the amygdala influence on DG LTP.

2. To investigate the effects of restraint stress and contextual fear condtioning on DG neurogenesis.

3. To study effects of repeated stress on DG neurogenesis and structure in relation to the amygdala and fear.

4. To determine the effects of stress and glucocorticoid manipulations on the expression and distribution of NMDA and other excitatory amino acid receptors in the dentate gyrus

5. To determine if turnover of DG neurons affects stability of fear conditioning.

6. To assess changes in DG gene expression during contextual fear conditioning.

7. To investigate the anatomical basis of hippocampal atrophy in the human brain with MRI and eventually compare this with animal brain MRI.


Suggested reading - listed below are some newer papers, and this list will be updated from time to time; in the "literature cited" section from the original grant application, the most important papers are identified by * or **.

Benmansour S, Cecchi M, Morilak. D.A., Gerhardt GA, Javors MA, Gould GG, Frazer A (1999) Effects of chronic antidepressant treatments on serotonin transporter function, density, and mRNA level. J. Neurosci. 19:10494-10501.

Cameron HA, McKay DG (1999) Restoring production of hippocampal neurons in old age. Nature Neurosci. 2:894-858.

Gould E (1999) Serotonin and hippocampal neurogenesis. Neuropsychopharmacology 21:46S-51S.

Gould, E., Beylin, A., Tanapat, P., Reeves, A., and Shors, T. J. (1999a) Learning enhances adult neurogenesis in the hippocampal formation. Nature Neurosci. 2, 260-265.

Gould E, Reeves AJ, Fallah M, Tanapat P, Gross CG (1999b) Hippocampal neurogenesis in adult Old World primates. Proc. Natl. Acad. Sci. USA 96:5263-5267.

Gould E, Reeves AJ, Graziano MSA, Gross CG (1999c) Neurogenesis in the neocortex of adult primates. Science 286:548-552.

Gould E, Tanapat P, Hastings NB, Shors TJ (1999d) Neurogenesis in adulthood: a possible role in learning. Trends in Cognitive Sciences 3:186-192.

Hastings NB, Gould E (1999) Rapid extension of axons into the CA3 region by adult-generated granule cells. J. Comp. Neurol. 413:146-154.

Kempermann G, Gage FH (1999a) Experience-dependent regulation of adult hippocampal neurogenesis: Effects of long-term stimulation and stimulus withdrawal. Hippocampus 9:321-332.

Kempermann G, Gage FH (1999b) New nerve cells for the adult brain. Sci. Am.48-53.

Roozendaal B, McGaugh JL (1997) Glucocorticoid receptor agonist and antagonist administration oito the basolateral but not central amygdala modulates memory storage. Neurobiology of Learning and Memory 67:176-179.

Roozendaal B, Nguyen BT, Power AE, McGaugh JL (1999) Basolateral amygdala noradrenergic influence enables enhancement of memory consolidaton induced by hippocampal glucocorticoid receptor activation. Proc. Natl. Acad. Sci. USA 96:11642-11647.

Sheline YI, Sanghavi M, Mintun MA, Gado MH (1999) Depression duration but not age predicts hippocampal volume loss in medically healthy women with recurrent major depression. J. Neurosci. 19:5034-5043.

Starkman MN, Giordani B, Gebrski SS, Berent S, Schork MA, Schteingart DE (1999) Decrease in cortisol reverses human hippocampal atrophy following treatment of Cushing's disease. Biol. Psychiat. 46:1595-1602.

Tanapat P, Hastings NB, Reeves AJ, Gould E (1999) Estrogen stimulates a transient increase in the number of new neurons in the dentate gyrus of the adult female rat. J. Neurosci. 19:5792-5801.

van Praag, H., Kempermann, G., and Gage, F. H. Running increases cell proliferation and neurogenesis in the adult mouse dentate gyrus. Nature Neurosci. 2, 266-270. 99.

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