Stress Leads to Contrasting Effects on the Levels of Brain Derived Neurotrophic Factor in the Hippocampus and Amygdala

Recent findings on stress induced structural plasticity in rodents have identified important differences between the hippocampus and amygdala. The same chronic immobilization stress (CIS, 2h/day) causes growth of dendrites and spines in the basolateral amygdala (BLA), but dendritic atrophy in hippocampal area CA3. CIS induced morphological changes also differ in their temporal longevity- BLA hypertrophy, unlike CA3 atrophy, persists even after 21 days of stress-free recovery. Furthermore, a single session of acute immobilization stress (AIS, 2h) leads to a significant increase in spine density 10 days, but not 1 day, later in the BLA. However, little is known about the molecular correlates of the differential effects of chronic and acute stress. Because BDNF is known to be a key regulator of dendritic architecture and spines, we investigated if the levels of BDNF expression reflect the divergent effects of stress on the hippocampus and amygdala. CIS reduces BDNF in area CA3, while it increases it in the BLA of male Wistar rats. CIS-induced increase in BDNF expression lasts for at least 21 days after the end of CIS in the BLA. But CIS-induced decrease in area CA3 BDNF levels, reverses to normal levels within the same period. Finally, BDNF is up regulated in the BLA 1 day after AIS and this increase persists even 10 days later. In contrast, AIS fails to elicit any significant change in area CA3 at either time points. Together, these findings demonstrate that both acute and chronic stress trigger opposite effects on BDNF levels in the BLA versus area CA3, and these divergent changes also follow distinct temporal profiles. These results point to a role for BDNF in stress-induced structural plasticity across both hippocampus and amygdala, two brain areas that have also been implicated in the cognitive and affective symptoms of stress-related psychiatric disorders

Epigenetic Regulation of BDNF Gene in Response to Stress

Neuronal plasticity induced by changes in synaptic morphology and function is well known to play a pivotal role in leaning and memory as well as adaptation to stress. It is suggested that these plastic changes are due to orchestration of alterations in gene expression in the brain. Recent advances in molecular biology have provided evidence that epigenetic mechanisms, such as DNA methylation and histone modification, are crucial to gene transcription in the mammalian brain. Our research group has recently investigated the involvement of histone actylation at the promoter of the brain-derived neurotrophic factor (BDNF) gene in stress-induced reduction in BDNF, as well as in fear conditioning-induced enhancement of BDNF, in the rat hippocampus. The results of the stress study demonstrated that single-immobilization stress significantly reduced the levels of total, exon I, and exon IV BDNF mRNA, and also significantly reduced acetylation levels of histone H3, but not H4, at the promoter of exons I, IV, and VI. The results of the fear conditioning study showed that footshock stress significantly increased the levels of total, exon I, and exon IV BDNF mRNA, with significantly increased acetylation levels of both histone H3 and H4, at the promoter of exons I and IV, followed by enhanced freezing to fear-context exposure. These findings suggest that changes in BDNF transcription in the rat hippocampus in response to stressful stimuli are, at least in part, regulated by histone acetylation status

Hyperactivation Of Bdnf-Trkb Signaling Cascades In Human Hypothalamic Hamartoma (Hh): A Potential Mechanism Contributing To Epileptogenesis

Aims: Although compelling evidence suggests that human hypothalamic hamartoma (HH) is intrinsically epileptogenic for gelastic seizures, the molecular mechanisms responsible for epileptogenesis within HH remain to be elucidated. The aim of this study was to test the hypothesis that hyperactivation of BDNF-TrkB signaling pathways in surgically resected HH tissue is a possible mechanism for downregulation of KCC2 expression, which in turn underlies GABA-mediated excitation within HH. Methods: Activation of three major BDNF-TrkB signaling pathways including MAPKs, Akt, and PLCγ1 were evaluated in surgically resected HH tissue (n = 14) versus human hypothalamic control tissue (n = 8) using combined methodologies of biochemistry, molecular biology, cell biology, and electrophysiology. Results: Our data show that compared with hypothalamic control tissue, in HH tissue, (i) activation of TrkB and expression of mature BDNF are elevated; (ii) MAPKs (including ERK1/2, p38, and JNK), Akt, and PLCγ1 are highly activated; (iii) KCC2 expression is downregulated; and (iv) pharmacological manipulation of TrkB signaling alters HH neuronal firing rate. Conclusion: Our findings suggest that multiple BDNF-TrkB signaling pathways are activated in HH. They act independently or collaboratively to downregulate KCC2 expression, which is the key component for GABA-mediated excitation associated with gelastic seizures

Deoxygedunin, a Natural Product with Potent Neurotrophic Activity in Mice

Gedunin, a family of natural products from the Indian neem tree, possess a variety of biological activities. Here we report the discovery of deoxygedunin, which activates the mouse TrkB receptor and its downstream signaling cascades. Deoxygedunin is orally available and activates TrkB in mouse brain in a BDNF-independent way. Strikingly, it prevents the degeneration of vestibular ganglion in BDNF −/− pups. Moreover, deoxygedunin robustly protects rat neurons from cell death in a TrkB-dependent manner. Further, administration of deoxygedunin into mice displays potent neuroprotective, anti-depressant and learning enhancement effects, all of which are mediated by the TrkB receptor. Hence, deoxygedunin imitates BDNF's biological activities through activating TrkB, providing a powerful therapeutic tool for treatment of various neurological diseases

Synergistic Activation of Dopamine D1 and TrkB Receptors Mediate Gain Control of Synaptic Plasticity in the Basolateral Amygdala

Fear memory formation is thought to require dopamine, brain-derived neurotrophic factor (BDNF) and zinc release in the basolateral amygdala (BLA), as well as the induction of long term potentiation (LTP) in BLA principal neurons. However, no study to date has shown any relationship between these processes in the BLA. Here, we have used in vitro whole-cell patch clamp recording from BLA principal neurons to investigate how dopamine, BDNF, and zinc release may interact to modulate the LTP induction in the BLA. LTP was induced by either theta burst stimulation (TBS) protocol or spaced 5 times high frequency stimulation (5xHFS). Significantly, both TBS and 5xHFS induced LTP was fully blocked by the dopamine D1 receptor antagonist, SCH23390. LTP induction was also blocked by the BDNF scavenger, TrkB-FC, the zinc chelator, DETC, as well as by an inhibitor of matrix metalloproteinases (MMPs), gallardin. Conversely, prior application of the dopamine reuptake inhibitor, GBR12783, or the D1 receptor agonist, SKF39393, induced robust and stable LTP in response to a sub-threshold HFS protocol (2xHFS), which does not normally induce LTP. Similarly, prior activation of TrkB receptors with either a TrkB receptor agonist, or BDNF, also reduced the threshold for LTP-induction, an effect that was blocked by the MEK inhibitor, but not by zinc chelation. Intriguingly, the TrkB receptor agonist-induced reduction of LTP threshold was fully blocked by prior application of SCH23390, and the reduction of LTP threshold induced by GBR12783 was blocked by prior application of TrkB-FC. Together, our results suggest a cellular mechanism whereby the threshold for LTP induction in BLA principal neurons is critically dependent on the level of dopamine in the extracellular milieu and the synergistic activation of postsynaptic D1 and TrkB receptors. Moreover, activation of TrkB receptors appears to be dependent on concurrent release of zinc and activation of MMPs

The Role of BDNF as a Mediator of Neuroplasticity in Bipolar Disorder

The cognitive impairment and neuroanatomical changes that takes place among patients with bipolar disorder (BD) patients has been well described. Recent data suggest that changes in neuroplasticity, cell resilience and connectivity are the main neuropathological findings in BD. Data from differential lines of research converges to the brain-derived neurotrophic factor (BDNF) as an important contributor to the neuroplasticity changes described among BD patients. BDNF serum levels have been shown to be decreased in depressive and manic episodes, returning to normal levels in euthymia. BDNF has also been shown to decrease as the disorder progresses. Moreover, factors that negatively influence the course of BD, such as life stress and trauma have been shown to be associated with a decrease in BDNF serum levels. These findings suggest that BDNF plays a central role in the progression of BD. The present review discusses the role of BDNF as a mediator of the neuroplastic changes that occur in portion with mood episodes and the potential use of serum BDNF as a biomarker in BD

A review on experimental and clinical genetic associations studies on fear conditioning, extinction and cognitive-behavioral treatment

Fear conditioning and extinction represent basic forms of associative learning with considerable clinical relevance and have been implicated in the pathogenesis of anxiety disorders. There is considerable inter-individual variation in the ability to acquire and extinguish conditioned fear reactions and the study of genetic variants has recently become a focus of research. In this review, we give an overview of the existing genetic association studies on human fear conditioning and extinction in healthy individuals and of related studies on cognitive-behavioral treatment (CBT) and exposure, as well as pathology development after trauma. Variation in the serotonin transporter (5HTT) and the catechol-o-methyltransferase (COMT) genes has consistently been associated with effects in pre-clinical and clinical studies. Interesting new findings, which however require further replication, have been reported for genetic variation in the dopamine transporter (DAT1) and the pituitary adenylate cyclase 1 receptor (ADCYAP1R1) genes, whereas the current picture is inconsistent for variation in the brain-derived neurotrophic factor (BDNF) gene. We end with a discussion of the findings and their limitations, as well as future directions that we hope will aid the field to develop further