Barry L. Jacobs, Ph.D. - US grants

This application is directed at better understanding how the brain serotonin system functions under normal conditions. Only through such an understanding will we be able to appreciate (and ameliorate) how its dysfunction is manifested in a variety of clinical pathologies, including, depression, anxiety, obsessive-compulsive disorders, and myoclonus. In order to achieve a necessary level of experimental precision, the proposed experiments focus on single cell recordings in behaving animals. Previous studies have characterized the activity of brain serotonergic neurons across the sleep-wake-arousal cycle, and their response to a variety of environmental and physiological challenges. The proposed studies will extend these analyses to an examination of the activity of these neurons during complex mammalian behavior. In particular, pilot experiments indicate that serotonergic neurons in the rostral (pontine) raphe groups are dramatically activated (2-5 fold) during central pattern generator (CPG) mediated rhythmic behaviors, especially those involving oral-buccal responses (chewing, licking, grooming). Reciprocally, the activity of many (all) of the same neurons is strongly inhibited during orienting responses (as indicated by head and eye movements, hippocampal theta activity, PGO waves, and heart rate deceleration). These initial observations will be tested rigorously, and expanded to encompass the caudal (medullary) group of serotonergic neurons. Three sets of studies are proposed, utilizing single unit recordings, multibarrel microiontophoresis, and in vivo brain microdialysis. I) SEROTONERGIC NEURONAL ACTIVITY AND CPG MEDIATED BEHAVIORS. a) Does a definitive positive relationship exist between the activity of pontine serotonergic neurons and rhythmic behaviors, especially those involving the oral-buccal region? b) Do the medullary groups of serotonergic neurons display a relation to rhythmic behaviors which does not include oral-buccal movements, but that does include movements mediated by more caudal aspects of the neuraxis? c) Are CPG-related increases in neuronal activity accompanied by increased release of serotonin preferentially in those brain regions directly related to the behavior? II) RELATION OF SEROTONERGIC NEURONAL ACTIVITY TO ORIENTING RESPONSES. a) Does a definitive inverse relationship exist between the activity of pontine, but not medullary, serotonergic neurons and orienting behavior? b) Is this decrease in neuronal activity related to eye or head movements, or to afferent inputs? III) ROLE OF THE SOMATODENDRITIC AUTORECEPTOR UPON SEROTONERGIC NEURONAL ACTIVITY UNDER PHYSIOLOGICAL CONDITIONS.

It is believed that visual perception occurs largely based on interactions of nerve cells, or neurons, in the visual cortex of the brain. The visual cortex itself is a structure composed of several layers of different classes on neurons. These classes are distinguished by the shape of the cells, their connections, their response to particular patterns of light stimulation or motion or color, and by the chemicals called neurotransmitters that the neurons secrete at their functional connections, called synapses. Two important neurotransmitters of a group called mono-amines are known as NE (norepinephrine) and 5-HT (5-hydroxy- tryptamine). The pathways for neurons in the brain to the cells they innervate are fairly well known for both these compounds, and monoamines are known to modulate activity in several neural systems. The equipment provided will allow a new approach to understanding modulation of cortical activity. The study is a preliminary effort to determine at the level of single cells in the well-described layers of the primate visual cortex, how information processing is modulated by the similarly layered and specifically connected neurons secreting monoamines. Highly controlled visual stimuli will be used to excite visual cortical cells, and when the responses are characterized, highly localized pharmacological applications of monoamines will be made by microelectrode. Changes in visual properties attributable to the monoamines which are specific to a cell class, lamina, or cortical area may be described in terms of their potential significance for perception and behavior. This work will have impact on psychology of arousal and attention, as well as on visual and sensory neuroscience, and provide a novel bridge between these communities.

DESCRIPTION (provided by applicant): A common result of chronic drug abuse is cognitive loss or dysfunction. In many of these cases no definitive neuropathology is associated with these deficits. A case in point is the cannabinoid drug, marijuana, whose use is most often associated with memory loss, following both acute and chronic intoxication. There is not, however, any definitive evidence of frank neuropathology associated with its use (cf. the drug "ecstasy" 3,4-MDMA). Recent evidence indicates that the mammalian brain (including humans) continues to produce new neurons into adulthood. Additionally, this process has been shown to be important in new learning and memory. This application proposes research which examines the effects of the delta-tetrahydrocannabinol (THC) on mitogenesis (cell proliferation), the first phase of neurogenesis, in the dentate gyrus (DG) of adult rats. These effects will also be studied in the context of their interaction with the proinflammatory cytokine interleukin-1beta (IL-1beta), which is released under a variety of infectious and stressful conditions. THC will be administered intraperitoneally both acutely and chronically in three doses. In addition, some of these animals will also be given IL-1beta chronically. Following these various drug treatments (or control treatments), all animals will be administered bromodeoxyuridine (BrdU) and sacrificed two hours later. The animals will be perfused and their brains removed and processed for BrdU-immunoreactivity. BrdU-labeled cells in the granule cell layer and hilus of the DG will be quantified using light microscopy. It is hypothesized that chronic, and possibly acute, THC will suppress DG mitogenesis and that the stress-related cytokine IL- 1beta will also have this effect. It is further hypothesized that the actions of the two compounds will be at least additive in suppressing DG mitogenesis.