The role of neurotrophic factors in adult hippocampal neurogenesis, antidepressant treatments and animal models of depressive-like behavior
ABSTRACT Major depressive disorder (MDD) is characterized by structural and neurochemical changes in limbic structures, including the hippocampus, that regulate mood and cognitive functions. Hippocampal atrophy is observed in patients with depression and this effect is blocked or reversed by antidepressant treatments. Brain-derived neurotrophic factor and other neurotrophic/growth factors are decreased in postmortem hippocampal tissue from suicide victims, which suggests that altered trophic support could contribute to the pathophysiology of MDD. Preclinical studies demonstrate that exposure to stress leads to atrophy and cell loss in the hippocampus as well as decreased expression of neurotrophic/growth factors, and that antidepressant administration reverses or blocks the effects of stress. Accumulating evidence suggests that altered neurogenesis in the adult hippocampus mediates the action of antidepressants. Chronic antidepressant administration upregulates neurogenesis in the adult hippocampus and this cellular response is required for the effects of antidepressants in certain animal models of depression. Here, we review cellular (e.g. adult neurogenesis) and behavioral studies that support the neurotrophic/neurogenic hypothesis of depression and antidepressant action. Aberrant regulation of neuronal plasticity, including neurogenesis, in the hippocampus and other limbic nuclei may result in maladaptive changes in neural networks that underlie the pathophysiology of MDD.
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- "author's copy Download Date | 4/28/15 6:38 AM remodeling has been relatively less well examined for the other hippocampal subfields, a few studies have observed dendritic retraction and decreases in spine density in CA1 and DG neurons following chronic stress (restraint stress 6 h daily, 21 days or 1 month of CUS) (Sousa et al., 2000; Pawlak et al., 2005; Christian et al., 2011) (Figure 1B). These stress-induced structural changes are thought to involve multiple mediators including elevated GC levels (Magariños and McEwen, 1995; Alfarez et al., 2008), CRH (Chen et al., 2010b) and reduced trophic support (reviewed in Schmidt and Duman, 2007). Pharmacological blockade of steroid synthesis (Magariños and McEwen, 1995) prior to stress exposure or the absence of the forebrain CRH1 receptor (CRHR1) (Wang et al., 2011a) renders animals resistant to chronic stress-mediated CA3 neuron dendritic atrophy. "
ABSTRACT: Exposure to stressors elicits a spectrum of responses that span from potentially adaptive to maladaptive consequences at the structural, cellular and physiological level. These responses are particularly pronounced in the hippocampus where they also appear to influence hippocampal-dependent cognitive function and emotionality. The factors that influence the nature of stress-evoked consequences include the chronicity, severity, predictability and controllability of the stressors. In addition to adult-onset stress, early life stress also elicits a wide range of structural and functional responses, which often exhibit life-long persistence. However, the outcome of early stress exposure is often contingent on the environment experienced in adulthood, and could either aid in stress coping or could serve to enhance susceptibility to the negative consequences of adult stress. This review comprehensively examines the consequences of adult and early life stressors on the hippocampus, with a focus on their effects on neurogenesis, neuronal survival, structural and synaptic plasticity and hippocampal-dependent behaviors. Further, we discuss potential factors that may tip stress-evoked consequences from being potentially adaptive to largely maladaptive.Reviews in the neurosciences 04/2015; DOI:10.1515/revneuro-2014-0083 · 3.31 Impact Factor
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- "In conclusion, our overall findings suggest that TH dysfunction can bidirectionally affect anxiety-and depression-like behaviors, likely through the regulation of hippocampal BDNF expression (Castren and Rantamaki, 2010; Cortes et al., 2012; Demet et al., 2002; Fukao et al., 2011; Schmidt and Duman, 2007). These findings provide new insights into the mechanism of depression and anxiety-like disorders induced by thyroid hormone dysfunction, which gives a potential target for clinical treatment of anxiety, depression and thyroid hormone disorders, especially when these disorders are comorbid (Freeman, 2009; Hyams et al., 2013). "
ABSTRACT: Thyroid hormone disorders have long been linked to depression, but the causal relationship between them remains controversial. To address this question, we established rat models of hypothyroidism using 131iodine (131I) and hyperthyroidism using levothyroxine (LT4). Serum free thyroxine (FT4) and triiodothyronine (FT3) significantly decreased in the hypothyroid of rats with single injections of 131I (5 mCi/kg). These rats exhibited decreased depression-like behaviors in forced swimming test and sucrose preference tests, as well as decreased anxiety-like behaviors in an elevated plus maze. Diminished levels of brain serotonin (5-HT) and increased levels of hippocampal brain-derived neurotrophic factor (BDNF) were found in the hypothyroid rats compared to the control saline-vehicle administered rats. LT4 treatment reversed the decrease in thyroid hormones and depression-like behaviors. In contrast, hyperthyroidism induced by weekly injections of LT4 (15 μg/kg) caused a greater than 10-fold increase in serum FT4 and FT3 levels. The hyperthyroid rats exhibited higher anxiety- and depression-like behaviors, higher brain 5-HT level, and lower hippocampal BDNF levels than the controls. Treatment with the antidepressant imipramine (15 mg/kg) diminished serum FT4 levels as well as anxiety- and depression-like behaviors in the hyperthyroid rats but led to a further increase in brain 5-HT levels, compared with the controls or the hypothyroid rats. Together, our results suggest that hypothyroidism and hyperthyroidism have bidirectional effects on anxiety- and depression-like behaviors in rats, possibly by modulating hippocampal BDNF levels.Hormones and Behavior 01/2015; 69C. DOI:10.1016/j.yhbeh.2015.01.003 · 4.51 Impact Factor
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- "This demonstrates that BDNF mediates the stimulation of neurogenesis and synaptogenesis by antidepressants . Similarly, central VEGF infusion increases cell proliferation and the survival of immature neurons (Jin et al., 2002; Warner-Schmidt and Duman, 2007). Further, VEGF knockout mice have lower levels of hippocampal cell proliferation and immature neurons (Sun et al., 2006), whereas viral-mediated VEGF overexpression has the opposite effect (Cao et al., 2004). "
ABSTRACT: The first half of this paper briefly reviews the evidence that (i) stress precipitates depression by damaging the hippocampus, leading to changes in the activity of a distributed neural system involving, inter alia, the amygdala, the ventromedial and dorsolateral prefrontal cortex, the lateral habenula and ascending monoamine pathways, and (ii) antidepressants work by repairing the damaged hippocampus, thus restoring the normal balance of activity within that circuitry. In the second half of the paper we review the evidence that heightened vulnerability to depression, either because of a clinical history of depression or because of the presence of genetic, personality or developmental risk factors, also confers resistance to antidepressant drug treatment. Thus, although antidepressants provide an efficient means of reversing the neurotoxic effects of stress, they are much less effective in conditions where vulnerability to depression is elevated and the role of stress in precipitating depression is correspondingly lower. Consequently, the issue of vulnerability should feature much more prominently in antidepressant research. Most of the current animal models of depression are based on the induction of a depressive-like phenotype by stress, and pay scant attention to vulnerability. As antidepressants are relatively ineffective in vulnerable individuals, this in turn implies a need for the development of different clinical and preclinical methodologies, and a shift of focus away from the current preoccupation with the hippocampus as a target for antidepressant action in vulnerable patients.Behavioural Pharmacology 09/2014; 25(5 and 6):352-371. DOI:10.1097/FBP.0000000000000066 · 2.19 Impact Factor