Hippocampal volume in primary unipolar major depression: a magnetic resonance imaging study

Vakili, Khashayar; Pillay, Srinivasan S.; Lafer, Beny; Fava, Maurizio; Renshaw, Perry F.; Bonello-Cintron, Christina M; Yurgelun‐Todd, Deborah

doi:10.1016/s0006-3223(99)00296-6

Cited by 334 publications

(193 citation statements)

References 11 publications

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“…In addition, reduction in the expression of endogenous BDNF has been shown to potentiate seizures induced by hippocampal kindling (Reibel et al 2000). The current work thus raises the possibility that reductions in hippocampal BDNF mRNA induced by uncondititioned stress or by re-exposure to cues previously paired with stress may be involved in the pathophysiology of hippocampus-dependent memory disturbances or decreases in hippocampal volume observed in stress-sensitive psychiatric disorders such as PTSD (Bremner et al 1995;Stein et al 1997;Gurvits et al 1996;Bremner et al 1997) and depression (Mervaala et al 2000;Vakili et al 2000). This also raises the possibility that unconditioned or psychological stress may facilitate the progression of dementing disorders such as Alzheimer's disease in which decreases in hippocampal BDNF levels (Hock et al 2000) and hippocampal volume (Laakso et al 2000) have been found.…”

Section: Discussionmentioning

confidence: 71%

“…Decreased expression of BDNF is hypothesized to play a role in the atrophy of hippocampal neurons in experimental animals in response to stress (Duman et al , 2000. Moreover, downregulation of BDNF could contribute to the hippocampal pathology observed in psychiatric disorders such as post-traumatic stress disorder (PTSD) and depression (Bremner et al 2000;Mervaala et al 2000;Vakili et al 2000). This possibility is supported by the observation that these disorders are sensitive to stressful experiences (Breslau et al 1995;Kendler et al 2000).…”

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confidence: 99%

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Downregulation of BDNF mRNA in the Hippocampal Dentate Gyrus after Re-exposure to Cues Previously Associated with Footshock,

Rasmusson

Shi

Duman

2002

Neuropsychopharmacology

233

109

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This study examined the effects of footshock stress and reexposure to cues previously associated with footshock on expression of brain-derived neurotrophic factor (BDNF) mRNA in the hippocampus of male rats. Exposure to twenty 0.5-s 0.4-mA footshocks co-terminating withBrain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family of growth factors, which also includes nerve growth factor and neurotrophins 3 and 4. BDNF as well as these other neurotrophins, plays an important role in neuronal growth and differentiation during development, and also contributes to the survival, function, and plasticity of neurons in the adult brain (Lewin and Barde 1996). Thus, through a variety of mechanisms in different brain regions, BDNF has been implicated in emergent phenomena such as learning and memory (Patterson et al. 1996;Mu et al. 1999) and even contributes to the modulation of overt behaviors such as aggression (Lyons et al. 1999). The ability of BDNF to influence these processes is related, in part, to the activity dependent regulation of BDNF expression in adult brain (Lewin and Barde 1996).BDNF is also thought to play a role in the cellular and behavioral responses to stress (Duman et al. , 2000. Exposure to physical stress, such as immobilization, downregulates BDNF expression in the hippocampus (Smith et al. 1995, Vaidya et al. 1997 (Duman et al. , 2000. Moreover, downregulation of BDNF could contribute to the hippocampal pathology observed in psychiatric disorders such as post-traumatic stress disorder (PTSD) and depression (Bremner et al. 2000;Mervaala et al. 2000;Vakili et al. 2000). This possibility is supported by the observation that these disorders are sensitive to stressful experiences (Breslau et al. 1995;Kendler et al. 2000). Based on these observations and findings, we became interested in determining whether psychological stress has a measurable impact on hippocampal BDNF expression similar to the effects of physical stressors that have been reported.We therefore tested the effects of psychological stress produced by exposures to cues previously paired with footshock on BDNF mRNA levels in the dentate gyrus of the hippocampus. We hypothesized that re-exposure to cues associated with footshock stress, as well as footshock itself, would decrease BDNF mRNA in the dentate gyrus. The results demonstrate that this type of psychological stress produces a heightened sensitivity to previously neutral cues that results in downregulation of BDNF, and suggest that psychological stress, such as that experienced in association with PTSD and depression, as well as other disorders, could result in decreased neurotrophic support of the hippocampus. MATERIAL AND METHODS AnimalsAdult male Sprague-Dawley rats were kept in a 12:12 h light-dark cycle (lights on at 7:00 A . M .) for 7-10 days before each experiment. The animals were housed two or three per cage and fed ad libitum. Experiments were conducted between 9:00 A . M . and 6:00 P . M . To control for possible effects of diurnal variation on hippoca...

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Section: Discussionmentioning

confidence: 71%

mentioning

confidence: 99%

Downregulation of BDNF mRNA in the Hippocampal Dentate Gyrus after Re-exposure to Cues Previously Associated with Footshock,

Rasmusson

Shi

Duman

2002

Neuropsychopharmacology

233

109

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“…A second irregularity in the hippocampus associated with depression is a reduction in hippocampal volume, with negative correlations between smaller volume and clinically relevant outcomes such as number of hospitalization for depression and number of lifetime days with depression (Bremner 2002;Bremner et al 2000;Mervaala et al 2000;Sheline et al 1999;Sheline et al 1996;Steffens et al 2000;Steffens and Krishnan 1998;Vakili et al 2000). Although an association has been suggested between a reduction in hippocampal volume and a decline in neurogenesis (Sheline 2003) the small number of neurons generated in the hippocampus is very unlikely to be able to influence the total volume of the hippocampus and thus an alternative mechanism is likely to be involved.…”

Section: Ra and The Hippocampusmentioning

confidence: 99%

The neurobiology of retinoic acid in affective disorders

Bremner

McCaffery

2008

Progress in Neuro-Psychopharmacology and Biological Psychiatry

142

154

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Current models of affective disorders implicate alterations in norepinephrine, serotonin, dopamine, and CRF/cortisol; however treatments targeted at these neurotransmitters or hormones have led to imperfect resolution of symptoms, suggesting that the neurobiology of affective disorders is incompletely understood. Until now retinoids have not been considered as possible contributors to affective disorders. Retinoids represent a family of compounds derived from Vitamin A that perform a large number of functions, many via the vitamin A product, retinoic acid. This signaling molecule binds to specific retinoic acid receptors in the brain which, like the glucocorticoid and thyroid hormone receptors, are part of the nuclear receptor superfamily and regulate gene transcription. Research in the field of retinoic acid in the CNS has focused on the developing brain, in part stimulated by the observation that isotretinoin (13-cis retinoic acid), an isomer of retinoic acid used in the treatment of acne, is highly teratogenic for the CNS. More recent work has suggested that retinoic acid may influence the adult brain; animal studies indicated that the administration of isotretinoin is associated with alterations in behavior as well as inhibition of neurogenesis in the hippocampus. Clinical evidence for an association between retinoids and depression includes case reports in the literature, studies of health care databases, and other sources. A preliminary PET study in human subjects showed that isotretinoin was associated with a decrease in orbitofrontal metabolism. Several studies have shown that the molecular components required for retinoic acid signaling are expressed in the adult brain ; the overlap of brain areas implicated in retinoic acid function and stress and depression suggest that retinoids could play a role in affective disorders. This report reviews the evidence in this area and describes several systems that may be targets of retinoic acid and which contribute to the pathophysiology of depression.

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“…In the amygdala, alterations in cerebral blood flow and metabolism, 6 asymmetry of amygdalar volumes, 7 as well as smaller [8][9][10] and larger volumes [11][12][13][14] have been observed in depressed subjects when compared with normal controls. In the hippocampus, volumetric analysis studies have also revealed reduced volumes in subjects suffering from major depression in some, 7,11,[14][15][16][17][18][19][20] but not all studies 10,[21][22][23] comparing depressed patients versus controls. Alterations in the cingulate cortex have also been observed by many authors.…”

Section: Introductionmentioning

confidence: 99%

Patterns of gene expression in the limbic system of suicides with and without major depression

et al. 2007

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The limbic system has consistently been associated with the control of emotions and with mood disorders. The goal of this study was to identify new molecular targets associated with suicide and with major depression using oligonucleotide microarrays in the limbic system (amygdala, hippocampus, anterior cingulate gryus (BA24) and posterior cingulate gyrus (BA29)). A total of 39 subjects were included in this study. They were all male subjects and comprised 26 suicides (depressed suicides = 18, non depressed suicides = 8) and 13 matched controls. Brain gene expression analysis was carried out on human brain samples using the Affymetrix HG U133 chip set. Differential expression in each of the limbic regions showed group-specific patterns of expression, supporting particular neurobiological mechanisms implicated in suicide and depression. Confirmation of genes selected based on their significance and the interest of their function with reverse transcriptase-polymerase chain reaction showed consistently correlated signals with the results obtained in the microarray analysis. Gene ontology analysis with differentially expressed genes revealed an overrepresentation of transcription and metabolism-related genes in the hippocampus and amygdala, whereas differentially expressed genes in BA24 and BA29 were more generally related to RNA-binding, regulation of enzymatic activity and protein metabolism. Limbic expression patterns were most extensively altered in the hippocampus, where processes related to major depression were associated with altered expression of factors involved with transcription and cellular metabolism. Additionally, our results confirm previous evidence pointing to global alteration of gabaergic neurotransmission in suicide and major depression, offering new avenues in the study and possibly treatment of such complex disorders. Overall, these data suggest that specific patterns of expression in the limbic system contribute to the etiology of depression and suicidal behaviors and highlight the role of the hippocampus in major depression.

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Hippocampal volume in primary unipolar major depression: a magnetic resonance imaging study

Cited by 334 publications

References 11 publications

Downregulation of BDNF mRNA in the Hippocampal Dentate Gyrus after Re-exposure to Cues Previously Associated with Footshock,

Downregulation of BDNF mRNA in the Hippocampal Dentate Gyrus after Re-exposure to Cues Previously Associated with Footshock,

The neurobiology of retinoic acid in affective disorders

Patterns of gene expression in the limbic system of suicides with and without major depression

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