Abstract

This is a proposal to test the general hypothesis that GABA plays an excitatory role in the developing hypothalamus of the rat, in contrast to its accepted role as an inhibitory neurotransmitter in the adult. Converging approaches utilizing fura-2 digital calcium imaging, immunocytochemistry and whole cell patch clamp recording will test five specific hypotheses using cultured neurons or hypothalamic slices. First, GABA is hypothesized to depolarize the membrane, increase neuronal activity, and increase intracellular calcium early, but not late, in development. Secondly, it is proposed that glutamate-mediated synaptic activity accelerates the maturation of the inhibitory actions of GABA seen in adults. Thirdly, the PI will test whether GABA is synthesized and released during early hypothalamic development. Fourthly, GABA is proposed to promote cell survival, increase synaptogenesis, influence cell motility, and increase neurite outgrowth in early development. Finally, do the inhibitory actions of GABA in the adult revert to inhibitory actions following neuronal injury? This reversion may have important consequences for how neurons respond to calcium-mediated toxicity and how they respond to GABA in general. Since many hypothalamic circuits are inhibitory and mediated by GABA in the adult, GABA's early excitatory actions may be crucial for normal development.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS034887-01
Application #
2274201
Study Section
Neurology B Subcommittee 2 (NEUB)
Project Start
1995-09-30
Project End
1999-09-29
Budget Start
1995-09-30
Budget End
1996-09-29
Support Year
1
Fiscal Year
1995
Total Cost
Indirect Cost

  Institution

Name
Yale University
Department
Surgery
Type
Schools of Medicine
DUNS #
082359691
City
New Haven
State
CT
Country
United States
Zip Code
06520

  Publications

Yao, Yang; Fu, Li-Ying; Zhang, Xiaobing et al. (2012) Vasopressin and oxytocin excite MCH neurons, but not other lateral hypothalamic GABA neurons. Am J Physiol Regul Integr Comp Physiol 302:R815-24
Fu, Li-Ying; van den Pol, Anthony N (2010) Kisspeptin directly excites anorexigenic proopiomelanocortin neurons but inhibits orexigenic neuropeptide Y cells by an indirect synaptic mechanism. J Neurosci 30:10205-19
Acuna-Goycolea, Claudio; Obrietan, Karl; van den Pol, Anthony N (2010) Cannabinoids excite circadian clock neurons. J Neurosci 30:10061-6
van den Pol, Anthony N (2010) Excitatory neuromodulator reduces dopamine release, enhancing prolactin secretion. Neuron 65:147-9
Acuna-Goycolea, Claudio; van den Pol, Anthony N (2009) Neuroendocrine proopiomelanocortin neurons are excited by hypocretin/orexin. J Neurosci 29:1503-13
van den Pol, Anthony N (2009) Viral infection leading to brain dysfunction: more prevalent than appreciated? Neuron 64:17-20
van den Pol, Anthony N; Ozduman, Koray; Wollmann, Guido et al. (2009) Viral strategies for studying the brain, including a replication-restricted self-amplifying delta-G vesicular stomatis virus that rapidly expresses transgenes in brain and can generate a multicolor golgi-like expression. J Comp Neurol 516:456-81
van den Pol, Anthony N; Yao, Yang; Fu, Li-Ying et al. (2009) Neuromedin B and gastrin-releasing peptide excite arcuate nucleus neuropeptide Y neurons in a novel transgenic mouse expressing strong Renilla green fluorescent protein in NPY neurons. J Neurosci 29:4622-39
Li, Ying; van den Pol, Anthony N (2009) Enhanced excitatory input to melanin concentrating hormone neurons during developmental period of high food intake is mediated by GABA. J Neurosci 29:15195-204
Fu, Li-Ying; van den Pol, Anthony N (2008) Agouti-related peptide and MC3/4 receptor agonists both inhibit excitatory hypothalamic ventromedial nucleus neurons. J Neurosci 28:5433-49

Showing the most recent 10 out of 66 publications