Jannon L. Fuchs - US grants

The long-term objective of the proposed research is to determine the role of neurotransmitter receptors in the mammalian circadian system. Receptors undergo up- and down-regulation, which may contribute to cyclic patterns of synaptic activity generated in the supreachiasmatic nucleus (SCN). The SCN contains several neurotransmitters and exhibits the two fundamental properties of a circadian clock: pacemaking and entrainment to the day-night cycle. Quantitative autoradiography of in vitro labeled brain sections will be used to characterize the distribution and circadian variation of a number of neurotransmitter receptors in the SCN and associated hypothalamic nuclei. Since light is the strongest entrainment cue, influences of the retinohypothalamic tract on SCN receptor levels will be examined. While daily variation in metabolic rate is already evident in the fetal and neonatal rat SCN, many endocrine and behavioral rhythms do not appear until 1-4 weeks after birth. Developmental patterns of neurotransmitter receptor distribution will be examined and considered in relation to anatomical development of the hypothalamus and the ontogeny of various endocrine and behavioral rhythms. The proposed research is essential for understanding the functional organization of developing and mature mammalian circadian systems. Furthermore, application of the information and techniques from this research will be valuable in testing the effectiveness and site of action of antidepressant drugs which alter the circadian characteristics of neurotransmitter receptor rhythms.

DESCRIPTION (from applicant's abstract): The proposed projects investigate the role of neurotransmitter receptor regulation, using a model system the rat whisker barrel cortex and GABA-A receptors, which mediate synaptic transmission for GABA, the major inhibitory neurotransmitter. A developmental peak in GABA-A receptors occurs before the major wave of GABA synaptogenesis, and at a time when the cortex is most vulnerable to excitation. We will test the hypothesis that GABA-A blockade during development will lead to: (1) neuron death, due to excitotixicty; and (2) fewer GABA-A receptors per neuron, because receptors are needed to establish effective synapses. GABA-A regulation in sensory deprivation may have a similar role in restoring the balance between excitation and inhibition that is necessary for proper cortical functioning. We have found that simply trimming a row of whiskers results in down-regulation GABA-A receptors in the corresponding cortical barrels, 3-4 synapses away. This decerase apparently has functional implications; whisker trimming and GABA-A blockade lead to the same neurophysiological signs of disinhibition. To investigate the cascade of events triggered by sensory deprivation, we will first work at the receptor end, examining whether GABA-A receptors change in number, subunit composition, or gene regulation. Finally, in considering what mediates the effects of sensory input on cortical GABA receptors, we propose brain-derived neurotrophic factor (BDNF) as an excellent candidate. We will test whether whisker trimming decreases BDNF, and whether mutant mice deficient in BDNF are compromised in their ability to regulate cortical GABA systems in response to sensory deprivation.