UCLA

Drugs of abuse and the environmental contextual stimuli that can predict their availability have long been known to influence behavior, leading to risk of relapse, one of the most difficult challenges facing those addicted to drugs. Addiction is thought to supplant the basal ganglia of the brain and its input structures, such that the concerted effort of the reward system is to make choices to obtain drugs, with environmental cues and internal states serving as driving forces. Because the phenomenon of addiction is rooted in interacting elements of reward circuits that involve many millions of neurons, as of yet, the neurophysiological correlates of the response of such large populations of neurons across the basal ganglia in vivo to conditioned drug cues and their functional interactions at rest are poorly understood. Although recording many neurons at once has become easier in recent years, the crux of the problem is finding meaning in such large datasets, especially in association with behavior. This dissertation is the first to examine frontostriatal circuits in addiction by recording in vivo from hundreds of neurons simultaneously in mouse medial prefrontal cortex and striatum and demonstrates neurophysiological correlates of drug cue-evoked pupil responses and interindividual variability in those responses. We also used those data in a novel way to assess hallmarks of neural criticality and system complexity in the cortex and striatum. This in itself represents another first in the fields of self-organized criticality and addiction.

The first two chapters of this dissertation describe the creation of a protocol for head- fixed high-density recording of neurons in multiple reward circuitry hubs in mice that exhibit a conditioned response to cocaine cues. We first showed that head-fixed mice can exhibit conditioned place preference for an odor context that was associated with cocaine injections in a virtual reality paradigm, indicative of a learned association. We also found that the response was quite variable between animals and rather than remaining in place, many animals tended to run when experiencing the drug context. Subsequently, we showed that in response to novel or drug-associated odors briefly presented to them, mice exhibit a range of locomotor responses, and neural firing may have encoded a representation of the cue or the locomotor response.

The last two chapters demonstrate the use of a 512-channel electrode array for recording the cortex and striatum simultaneously in conjunction with pupillometry and cocaine conditioning. Pupillometry allowed us to assess the CR and have a behavioral readout that does not interfere with interpretation of physiology as well as track interindividual variability in cue responsiveness. We found that frontostriatal circuit dynamics correlate with cocaine cue-evoked behavioral arousal during early abstinence in mice. Small amounts of cortical pyramidal neuron hyperactivity, rather than hypoactivity during quiescence, was also observed. We then describe several aspects of universal critical dynamics and complexity in our datasets and how they relate to interindividual variability in our pupillary data and hyperactivity. We show that cocaine treatment enhances critical tuning and complexity in the cortex, while decoupling both phenomena in cortex and striatum, showing that there are real quantitative effects of drug usage on critical neural networks and system state variables.