Office of the Chief

Section on In Vivo Neural Function

Section on Neuronal Structure

Section on Synaptic Pharmacology

The Section on In Vivo Neural Function focuses on the relationship between corticostriatal dysfunction and neurodegenerative and psychiatric disorders in order to better understand the neurobiology of learning through trial and error. Much of the Section’s work involves mice that were trained to press a lever eight times to receive a reward. Mice were implanted with electrode arrays that targeted the dorsal striatum and the substantia nigra in order to determine which neurons fired during the initiation, middle and termination of the sequence of lever presses. Results showed that different neurons were involved in the three different stages. The Section further examined the neurobiological mechanisms of learning by studying knockout mice that lacked the NMDAR1 subunit of the NMDA receptor. Compared with controls, these mice were significantly less able to learn that they would be rewarded if they pressed the lever 8 times. These results suggest that striatal circuits are necessary to learn and crystallize specific action sequences.

The Section on Neuronal Structure studies how drugs of abuse change synapse and neuronal connectivity in brain, and it focuses on the short and long term actions on synaptic transmission in the nucleus accumbens (NAc) and the ventral tegmental area (VTA). The Section is especially interested in how cocaine and ethanol exposure alters neurons in these regions. Studies on the effects of cocaine withdrawal following long and short-term cocaine administration in mice have yielded the following observations: cocaine withdrawal is not required for the development of plasticity in the NAc because functional and morphological changes were detected immediately after prolonged cocaine administration; and medium spiny neurons expressing dopamine D1-receptors in the core of the NAc are particularly susceptible to cocaine-induced plasticity. Other studies on chronic drinking in monkeys and “binge drinking” in mice are uncovering the neurobiological effects of ethanol. The Section has also examined the functional and morphological differences that underwrite a predisposition for cocaine addiction. Mice were trained to perform a task to receive intravenous doses of cocaine, and they were observed for indications of operationalized measures of perseverance, motivation and adverse consequences (i.e., key drug-seeking behaviors). Less than one third of the mice scored positive for one of these indicators and only 6% scored positive for all three. The Section is now conducting further studies to determine if characteristic “binge” behaviors are predictive of subsequent addiction.

The Section on Synaptic Pharmacology focuses on the role of striatal neuronal activity and synaptic plasticity on learning and memory. Much of the Section’s work examines changes in the dorsomedial striatum (DMS) and dorsolateral striatum (DLS) of mice who are trained to balance on an accelerating rotarod. The Section tested the excitatory postsynaptic potential (EPSP) of brain slices of mice trained for 1 and 8 days. EPSPs in the DMS of mice trained for one day were significantly higher than those in controls, and EPSPs in the DLS of mice trained for 8 days were significantly higher than those in controls. However, EPSPS in the DMS of mice trained for 8 days and EPSPs in the DLS of mice trained for 1 day did not differ significantly from controls. These and other experiments suggest a shift in the locus of control from the DMS to the DLS as learning proceeds from initial to late stages. The Section is also involved in studies on the effects of endocannabinoids (eCB) and serotonin on long-term depression (LTD) of synaptic strength. In vitro experiments show that eCB-dependent LTD occurs in GABAeric and glutamateric synapses. However, moderate frequency synaptic input causes GABAergic eCB-dependent LTD, and net output is decreased by glutamateric eCB-dependent LTD at higher activation frequencies. Furthermore, the activation of serotonin receptors initiates LTD, which is independent of receptor activation.