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Department of Psychiatry
Department of Neuroscience
855 N. Wolfe Street
Baltimore, MD 21205
Regulation of experience-dependent gene expression in brain circuits that control behavior
The importance of brain-derived neurotrophic factor (BDNF) signaling in numerous brain processes, including cognition, learning and memory is undisputed. Indeed, intact BDNF signaling is deemed critical for normal brain function, and is disrupted in many neuropsychiatric and neurodevelopmental disorders. Stimulating BDNF production is proposed therapeutically in a number of disorders, but since BDNF and its cognate receptor TrkB are widely expressed in multiple cell types and brain regions, global stimulation strategies suffer from a lack of specificity. The BDNF gene has nine 5’ untranslated region exons, each containing a unique promoter. These promoters drive transcription of BDNF variants that contain different regulatory sequence, but encode a similar protein. Isoforms show distinct expression patterns suggesting localization in discrete circuits. Since they produce a similar protein, individual transcripts may serve similar molecular roles, but be activated in cell populations that are dedicated to distinct brain functions. This has led to the hypothesis that BDNF isoforms may have discrete, rather than redundant, roles in brain function. Such a BDNF transcriptional “code” could provide tight temporal and spatial control of BDNF signaling and downstream plasticity in discrete subpopulations of neurons, allowing a single cell-signaling pathway to mediate a myriad of functions. If distinct transcripts are expressed in circuits that control specific brain functions, those transcripts may represent more selective therapeutic targets.
Using mice in which we selectively disrupted BDNF expression from individual promoters, we demonstrated that “BDNF-related phenotypes” (e.g. aggression; obesity; fear extinction; reversal learning; and stress/depression susceptibility) segregate with loss of expression from distinct promoters. Our current approach uses mouse genetics in combination with molecular, cellular and systems-level techniques to define the specific role of BDNF splice variants in discrete microcircuits that control circuit activity and behavior. By quantifying expression of individual BDNF transcripts at the single cell level, we discovered that transcript-specific activation of BDNF expression occurs in discrete neuronal ensembles, which we can identify and access during behavior. We have developed a set of genetic and viral tools to functionally manipulate these neuronal ensembles to understand how they regulate specific brain circuits that control behavior.
Maynard KR, Hobbs JW, Sukumar M, Kardian AS, Jimenez DV, Schloesser, Martinowich K, "Bdnf mRNA splice variants differentially impact CA1 and CA3 dendrite complexity and spine morphology in the hippocampus", Brain, Structure & Function, EPub ahead of print March 2017.
Hill JL, Hardy NF, Jimenez DV, Maynard KR, Kardian AS, Pollock CJ, Schloesser, Martinowich K, "Loss of promoter IV-driven BDNF expression impacts oscillatory activity during sleep, sensory information processing and fear regulation", Translational Psychiatry, 6(8):e873, 2016.
Maynard KR, Hill JL, Calcaterra NE, Palko ME, Kardian A, Paredes D, Sukumar M, Adler BD, Jimenez DV, Schloesser RJ, Tessarollo L, Lu B, Martinowich K, "Functional role of BDNF production from unique promoters in aggression and serotonin signaling", Neuropsychopharmacology, 41(8), 1943-55, 2016.
Schloesser RJ, Orvoen S, Jimenez DV, Hardy NF, Maynard KR, Sukumar M, Manji HK, Gardier AM, David DJ, Martinowich K, “Antidepressant-like effects of electroconvulsive seizures require adult neurogenesis in a neuroendocrine model of depression”, Brain Stimulation, 8(5), 862-7, 2015.
Gao M, Maynard KR, Chokshi V, Song L, Jacobs C, Wang H, Tran T, Martinowich K, Lee HK, “Rebound potentiation of inhibition in juvenile visual cortex requires vision-induced BDNF expression”, Journal of Neuroscience, 34(32), 10770-9, 2014.
Schloesser RJ, Jimenez DV, Hardy NF, Paredes D, Catlow BJ, Manji HK, McKay RD, Martinowich K, “Atrophy of pyramidal neurons and increased stress-induced glutamate levels in CA3 following chronic suppression of adult neurogenesis”, Brain Structure Function, 219(3), 1139-48, 2014.
Martinowich K, Schloesser RJ, Lu Y, Jimenez DV, Paredes D, Greene JS, Greig NH, Manji HK, Lu B, "Roles of p75NTR, long-term depression and cholinergic transmission in anxiety and acute stress coping", Biological Psychiatry, 71(1),75-83, 2012.
Martinowich K, Schloesser RJ, Jimenez DV, Weinberger DR, Lu B, “Activity-dependent brain-derived neurotrophic factor expression regulates cortistatin-interneurons and sleep behavior”, Molecular Brain, 4(11), 2011.
Fritsch B, Reis J, Martinowich K, Schambra HM, Ji Y, Cohen LG, Lu B, "Direct current stimulation promotes BDNF-dependent synaptic plasticity: potential implications for motor learning", Neuron, 66(2), 198-204, 2010.
Schloesser RJ, Lehmann M, Martinowich K, Manji HK, Herkenham M, "Environmental enrichment requires adult neurogenesis to facilitate the recovery from psychosocial stress", Molecular Psychiatry, 15(12), 1152-63, 2010.
Schloesser RJ, Manji HK, Martinowich K, "Suppression of adult neurogenesis leads to an increased hypothalamo-pituitary-adrenal axis response", NeuroReport, 20(6), 553-557, 2009.
Fan G, Martinowich K, Chin MH, He F, Fouse SD, Hutnick L, Hattori D, Ge W, Shen Y, Wu H, ten-Hoeve J, Shuai K, Sun YE, "DNA methylation controls the timing of astrogliogenesis through regulation of JAK-STAT signaling", Development, 132(15), 3345-3346, 2005.
Martinowich K, Hattori D, Wu H, Fouse S, He F, Hu Y, Fan G, Sun YE, "DNA methylation-related chromatin remodeling in activity-dependent BDNF gene regulation", Science, 302(5646), 890-893, 2003.