INTRINSIC MEMBRANE ADAPTATIONS TO COCAINE EXPOSURE AND SLEEP DEPRIVATION

Bradley Winters

The intrinsic membrane properties of neurons integrate excitatory and inhibitory synaptic inputs and help determine action potential output. Cellular adaptations in intrinsic membrane excitability (IME) in response to a wide range of factors are an important determinant of behavioral outcome. Chapter 1 explores changes in IME of deep layer pyramidal cells of the prefrontal cortex in response to sleep deprivation (SD). Despite sleep-loss-induced cognitive deficits, little is known about the cellular adaptations that occur with SD. We used brain slices obtained from mice that were sleep deprived for 8 h to examine the electrophysiological effects of SD. We employed a modified pedestal (flowerpot) over water method for SD that eliminated rapid eye movement sleep and greatly reduced non-rapid eye movement sleep. In layer V/VI pyramidal cells of the medial prefrontal cortex, miniature excitatory post synaptic current amplitude was slightly reduced, miniature inhibitory post synaptic currents were unaffected, and intrinsic membrane excitability was increased after SD. These data suggest that SD may modulate the output of the PFC. Chapter 2 explores changes in IME of cannabinoid receptor 1 (CB1)-expressing fast spiking interneurons (FSIs) of the nucleus accumbens (NAc) in response to passive cocaine exposure. Endocannabinoid signaling critically regulates emotional and motivational states via activation CB1 in the brain. The NAc functions to gate emotional and motivational responses. Although expression of CB1 in cells intrinsic to the NAc is low, manipulation of CB1-signaling within the NAc triggers robust emotional/motivational alterations related to drug addiction and other psychiatric disorders, and these effects cannot be exclusively attributed to CB1 located at afferents to the NAc. Rather, CB1-expressing neurons in the NAc, although sparse, appear to be critical for emotional and motivational responses. However, the cellular properties of these neurons remain largely unknown. We generated a knock-in mouse line in which CB1-expressing neurons produce the fluorescent protein td-Tomato (tdT). We found that CB1-expressing neurons within the NAc are exclusively fast-spiking interneurons (FSIs). The membrane excitability of CB1-FSIs in the NAc was up-regulated following cocaine exposure suggesting that the basal functional output of the NAc is inhibited during cocaine withdrawal by multiple mechanisms.

INTRINSIC MEMBRANE ADAPTATIONS TO COCAINE EXPOSURE AND SLEEP DEPRIVATION

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