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.
"In the stress model, the decreased BDNF expression was observed in the hippocampus (Duman, 2009) and also in the cortical and subcortical regions of lab animals (Pizarro et al., 2004). The diminished BDNF expression was correlated with lower neurogenesis (Schmidt and Duman, 2007) and symptoms of depressive behavior (Taliaz et al., 2010). Moreover, BDNF has been proposed to participate in stress response by modifying the HPA axis activity (Tapia-Arancibia et al., 2004; Givalois et al., 2004; Neuropeptides xxx (2015) xxx–xxx ⁎ Corresponding author at: Laboratory of Molecular Biology, Faculty of Physiotherapy, The Jerzy Kukuczka Academy of Physical Education, Mikolowska 72 a, 40-065 Katowice, Poland. "
"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. "
[Show abstract][Hide abstract] 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 · 3.33 Impact Factor
"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). "
[Show abstract][Hide abstract] 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 · 4.63 Impact Factor
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