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2.
Mol Psychiatry ; 22(10): 1370-1375, 2017 10.
Article in English | MEDLINE | ID: mdl-28937692

ABSTRACT

Neurotrophic factors, a family of secreted proteins that support the growth, survival and differentiation of neurons, have been intensively studied for decades due to the powerful and diverse effects on neuronal physiology, as well as their therapeutic potential. Such efforts have led to a detailed understanding on the molecular mechanisms of neurotrophic factor signaling. One member, brain-derived neurotrophic factor (BDNF) has drawn much attention due to its pleiotropic roles in the central nervous system and implications in various brain disorders. In addition, recent advances linking the rapid-acting antidepressant, ketamine, to BDNF translation and BDNF-dependent signaling, has re-emphasized the importance of understanding the precise details of BDNF biology at the synapse. Although substantial knowledge related to the genetic, epigenetic, cell biological and biochemical aspects of BDNF biology has now been established, certain aspects related to the precise localization and release of BDNF at the synapse have remained obscure. A recent series of genetic and cell biological studies have shed light on the question-the site of BDNF release at the synapse. In this Perspectives article, these new insights will be placed in the context of previously unresolved issues related to BDNF biology, as well as how BDNF may function as a downstream mediator of newer pharmacological agents currently under investigation for treating psychiatric disorders.


Subject(s)
Brain-Derived Neurotrophic Factor/metabolism , Brain-Derived Neurotrophic Factor/physiology , Animals , Antidepressive Agents/pharmacology , Brain/metabolism , Brain-Derived Neurotrophic Factor/genetics , Humans , Ketamine/pharmacology , Neuronal Plasticity/genetics , Neurons/metabolism , Signal Transduction/drug effects , Synapses/metabolism
3.
Transl Psychiatry ; 6(8): e873, 2016 08 23.
Article in English | MEDLINE | ID: mdl-27552586

ABSTRACT

Posttraumatic stress disorder is characterized by hyperarousal, sensory processing impairments, sleep disturbances and altered fear regulation; phenotypes associated with changes in brain oscillatory activity. Molecules associated with activity-dependent plasticity, including brain-derived neurotrophic factor (BDNF), may regulate neural oscillations by controlling synaptic activity. BDNF synthesis includes production of multiple Bdnf transcripts, which contain distinct 5' noncoding exons. We assessed arousal, sensory processing, fear regulation and sleep in animals where BDNF expression from activity-dependent promoter IV is disrupted (Bdnf-e4 mice). Bdnf-e4 mice display sensory hyper-reactivity and impaired electrophysiological correlates of sensory information processing as measured by event-related potentials (ERP). Utilizing electroencephalogram, we identified a decrease in slow-wave activity during non-rapid eye movement sleep, suggesting impaired sleep homeostasis. Fear extinction is controlled by hippocampal-prefrontal cortical BDNF signaling, and neurophysiological communication patterns between the hippocampus (HPC) and medial prefrontal cortex (mPFC) correlate with behavioral performance during extinction. Impaired fear extinction in Bdnf-e4 mice is accompanied by increased HPC activation and decreased HPC-mPFC theta phase synchrony during early extinction, as well as increased mPFC activation during extinction recall. These results suggest that activity-dependent BDNF signaling is critical for regulating oscillatory activity, which may contribute to altered behavior.


Subject(s)
Arousal/genetics , Brain Waves/genetics , Brain-Derived Neurotrophic Factor/genetics , Evoked Potentials/genetics , Sleep/genetics , Stress Disorders, Post-Traumatic/genetics , Animals , Arousal/physiology , Brain Waves/physiology , Brain-Derived Neurotrophic Factor/metabolism , Electroencephalography , Evoked Potentials/physiology , Extinction, Psychological/physiology , Fear/physiology , Hippocampus/physiopathology , Mice , Prefrontal Cortex/physiopathology , Prepulse Inhibition , Promoter Regions, Genetic , Reflex, Startle , Sleep/physiology , Stress Disorders, Post-Traumatic/physiopathology , Theta Rhythm/genetics , Theta Rhythm/physiology
4.
Mol Psychiatry ; 18(8): 856-63, 2013 Aug.
Article in English | MEDLINE | ID: mdl-23689537

ABSTRACT

Available treatments for depression have significant limitations, including low response rates and substantial lag times for response. Reports of rapid antidepressant effects of a number of compounds, including the glutamate N-methyl-D-aspartate receptor antagonist ketamine, have spurred renewed translational neuroscience efforts aimed at elucidating the molecular and cellular mechanisms of action that result in rapid therapeutic response. This perspective provides an overview of recent advances utilizing compounds with rapid-acting antidepressant effects, discusses potential mechanism of action and provides a framework for future research directions aimed at developing safe, efficacious antidepressants that achieve satisfactory remission not only by working rapidly but also by providing a sustained response.


Subject(s)
Antidepressive Agents/pharmacology , Antidepressive Agents/therapeutic use , Ketamine/pharmacology , Ketamine/therapeutic use , Signal Transduction/drug effects , Animals , Excitatory Amino Acid Antagonists/pharmacology , Excitatory Amino Acid Antagonists/therapeutic use , Humans , Models, Neurological , Time Factors
5.
Mol Psychiatry ; 17(11): 1130-42, 2012 Nov.
Article in English | MEDLINE | ID: mdl-21912391

ABSTRACT

Women are twice as likely as men to develop major depressive disorder (MDD) and are more prone to recurring episodes. Hence, we tested the hypothesis that the illness may associate with robust molecular changes in female subjects, and investigated large-scale gene expression in the post-mortem brain of MDD subjects paired with matched controls (n=21 pairs). We focused on the lateral/basolateral/basomedian complex of the amygdala as a neural hub of mood regulation affected in MDD. Among the most robust findings were downregulated transcripts for genes coding for γ-aminobutyric acid (GABA) interneuron-related peptides, including somatostatin (SST), tachykinin, neuropeptide Y (NPY) and cortistatin, in a pattern reminiscent to that previously reported in mice with low brain-derived neurotrophic factor (BDNF). Changes were confirmed by quantitative PCR and not explained by demographic, technical or known clinical parameters. BDNF itself was significantly downregulated at the RNA and protein levels in MDD subjects. Investigating putative mechanisms, we show that this core MDD-related gene profile (including SST, NPY, TAC1, RGS4 and CORT) is recapitulated by complementary patterns in mice with constitutive (BDNF-heterozygous) or activity-dependent (exon IV knockout) decreases in BDNF function, with a common effect on SST and NPY. Together, these results provide both direct (low RNA/protein) and indirect (low BDNF-dependent gene pattern) evidence for reduced BDNF function in the amygdala of female subjects with MDD. Supporting studies in mutant mice models suggest a complex mechanism of low constitutive and activity-dependent BDNF function in MDD, particularly affecting SST/NPY-related GABA neurons, thus linking the neurotrophic and GABA hypotheses of depression.


Subject(s)
Amygdala/metabolism , Brain-Derived Neurotrophic Factor/genetics , Depressive Disorder, Major/genetics , GABAergic Neurons/metabolism , Adolescent , Adult , Aged , Animals , Brain-Derived Neurotrophic Factor/biosynthesis , Case-Control Studies , Down-Regulation/genetics , Female , Gene Expression Profiling/methods , Genetic Association Studies/methods , Humans , Mice , Mice, Knockout , Middle Aged , Neuropeptide Y/genetics , Neuropeptides/genetics , Somatostatin/genetics , Tachykinins/genetics
6.
Mol Psychiatry ; 15(12): 1152-63, 2010 Dec.
Article in English | MEDLINE | ID: mdl-20308988

ABSTRACT

The subgranular zone of the adult hippocampal dentate gyrus contains a pool of neural stem cells that continuously divide and differentiate into functional granule cells. It has been shown that production of new hippocampal neurons is necessary for amelioration of stress-induced behavioral changes by antidepressants in animal models of depression. The survival of newly born hippocampal neurons is decreased by chronic psychosocial stress and increased by exposure to enriched environments. These observations suggest the existence of a link between hippocampal neurogenesis, stress-induced behavioral changes, and the beneficial effects of enriched environment. To show causality, we subjected transgenic mice with conditionally suppressed neurogenesis to psychosocial stress followed by environmental enrichment. First, we showed that repeated social defeat coupled with chronic exposure to an aggressor produces robust and quantifiable indices of submissive and depressive-like behaviors; second, subsequent exposure to an enriched environment led to extinction of the submissive phenotype, while animals exposed to an impoverished environment retained the submissive phenotype; and third, enrichment was not effective in reversing the submissive and depressive-like behaviors in transgenic mice lacking neurogenesis. Our data show two main findings. First, living in an enriched environment is highly effective in extinguishing submissive behavioral traits developed during chronic social stress, and second, these effects are critically dependent on adult neurogenesis, indicating that beneficial behavioral adaptations are dependent on intact adult neurogenesis.


Subject(s)
Adaptation, Physiological , Adult Stem Cells/cytology , Environment , Neural Stem Cells/cytology , Neurogenesis/physiology , Stress, Psychological/psychology , Adaptation, Psychological , Adult Stem Cells/physiology , Analysis of Variance , Animals , Cell Differentiation , Cell Tracking/methods , Dentate Gyrus/cytology , Depression/physiopathology , Depression/psychology , Disease Models, Animal , Dominance-Subordination , Female , Housing, Animal , Male , Mice , Mice, Inbred C57BL , Mice, Transgenic , Neural Stem Cells/physiology , Resilience, Psychological , Stress, Psychological/physiopathology
7.
Semin Cell Dev Biol ; 14(3): 161-8, 2003 Jun.
Article in English | MEDLINE | ID: mdl-12948350

ABSTRACT

Neural stem cells (NSCs) are subscribed extraordinary potential in repair of the damaged nervous system. However, the molecular identity of NSCs has not been established. Most NSC cultures contain large numbers of multipotent, bipotent, and lineage restricted neural progenitors, the majority of which appear to lose neurogenic potential after expansion. This review first discusses the neurogenic to gliogenic switch that is characteristic of progenitor development in vivo and in NSC cultures, and then the cell intrinsic and extrinsic mechanisms regulating the sequential differentiation of neurons and glia. Finally, we discuss potential methods for maintaining the neurogenic potential of NSC cultures after expansion.


Subject(s)
Brain/cytology , Brain/physiology , Nerve Regeneration/physiology , Signal Transduction/physiology , Animals , Brain/embryology , Humans , Mammals , Neuroglia/physiology , Neurons/physiology , Stem Cells/physiology
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