Medial prefrontal cortex (mPFC) is involved in relapse after withdrawal for cocaine exposure, but changes in synaptic function and plasticity in the mPFC during the period of withdrawal remain largely unknown. After the termination of repeated cocaine treatments in rats, I observed a gradual enhancement in the susceptibility of excitatory synapses on layer V mPFC pyramidal neurons to activity-induced long-term potentiation (LTP). This enhanced synaptic plasticity could be attributed to a gradual increase in the expression of brain-derived neurotrophic factor (BDNF) and its suppression of GABAergic inhibition in the mPFC via reducing the surface expression of GABAA receptors. The BDNF effect is mediated by TrkB activation in these neurons and accompanied by elevated protein phosphatase 2A activity and increased de-phosphorylation of GABAA receptor beta3 subunit in the mPFC. Thus, elevated BDNF expression during cocaine withdrawal sensitizes the excitatory inputs in the mPFC for activity-induced persistent synaptic potentiation that may contribute to cue-induced drug craving and seeking.

Prenatal cocaine-exposed new-born babies could be considered as undergoing withdrawal from cocaine exposure in utero. Previous studies have shown that prenatal cocaine exposure results in abnormal brain development and cognitive dysfunction, but the underlying cellular mechanism remains largely unclear. I proposed the hypothesis that prenatal cocaine exposure may cause similar modification of synaptic plasticity in the mPFC as that found in above cocaine withdrawal studies in juvenile rats. Thus, in the second part of my study, I examined synaptic functions in the mPFC of postnatal rats which were exposed to cocaine in utero, using whole-cell recording from mPFC layer V pyramidal neurons in acute brain slices. I found that cocaine exposure in utero also resulted in a facilitated LTP of excitatory synapses on these pyramidal neurons and an elevated neuronal excitability in postnatal rat pups after P15. This facilitated LTP could be largely attributed to the reduction of GABAergic inhibition. Biochemical assays of isolated mPFC tissue from postnatal rats further showed that cocaine exposure in utero caused a marked reduction in the surface expression of GABAA receptor subunits alpha1, beta2, and beta3, but had no effect on glutamate receptor subunit GluR1. Both facilitated LTP and reduced surface expression of GABAA receptors persisted in rats up to at least P42. Finally, the behavioral consequence of cocaine exposure in utero was reflected by the reduction in the sensitivity of locomotor activity in postnatal rats to cocaine and the dopamine receptor agonist apomorphine. Since the mPFC plays important roles in cognitive functions, these findings offer new insights into the cellular mechanism underlying the adverse effects of cocaine exposure in utero on brain development and cognitive functions.

In summary, this thesis work showed that excitatory inputs to mPFC layer V pyramidal neurons are sensitized for activity-induced persistent synaptic potentiation due to the reduction of GABAergic inhibition after withdrawal from repeated cocaine exposure either in utero or after birth. These findings have increased our understanding of the neurobiological basis of cocaine addiction and may help to establish more thorough pharmacological treatments for cocaine addiction.

An essential step in understanding visual processing is to characterize the neuronal receptive fields (RFs) at each stage of the visual pathway. However, RF characterization beyond simple cells in the primary visual cortex (V1) remains a major challenge. Recent application of spike-triggered covariance (STC) analysis has greatly facilitated characterization of complex cell RFs in anesthetized animals. Here we apply STC to RF characterization in awake monkey V1. We found up to nine subunits for each cell, including one or two dominant excitatory subunits as described by the standard model, along with additional excitatory and suppressive subunits with weaker contributions. Compared with the dominant subunits, the nondominant excitatory subunits prefer similar orientations and spatial frequencies but have larger spatial envelopes. They contribute to response invariance to small changes in stimulus orientation, position, and spatial frequency. In contrast, the suppressive subunits are tuned to orientations 45 degrees - 90 degrees different from the excitatory subunits, which may underlie cross-orientation suppression. Together, the excitatory and suppressive subunits form a compact description of RFs in awake monkey V1, allowing prediction of the responses to arbitrary visual stimuli.