UCSF

How neurons in the mammalian brain give rise to complex behaviors is a fundamental challenge in neuroscience research. Circuits in the prefrontal cortex (PFC) direct higher-order cognitive and motivated behaviors such as decision-making and impulse control, and dysfunction of these circuits gives rise to neuropsychiatric disorders such as schizophrenia, anxiety disorders, and autism. Recent studies and new technologies have fueled a renaissance in understanding the function of these circuits by using neuronal subtypes as entry points into these circuits, but our knowledge of how these circuits function remains limited. In this dissertation, three studies are presented that advance new insights regarding the cellular connectivity, composition, and network information processing of subtypes of inhibitory neurons. In the first study, we examined how inhibition differs between projection-specific pyramidal neurons in layer 5 of PFC. Using in vitro patch-clamp electrophysiology and optogenetics, we found that subcortically-projecting pyramidal neurons receive significantly greater inhibition than callosally-projecting pyramidal neurons. This selective inhibition is likely attributed to increased inhibition from parvalbumin (PV) interneurons onto the subcortically-projecting pyramidal neurons, since optogenetic activation of another interneuron subtype, the somatostatin (SOM) interneuron, did not reveal differences in inhibition. In the second study, we challenged the definition that all inhibitory neurons are “interneurons”, that is that they only target neighboring neurons in the local circuit and do not form distant connections with neurons in other brain regions. Using transgenic mouse lines in combination with viral tracing and in vitro patch-clamp electrophysiology, we found a population of prefrontal inhibitory neurons with long-range projections distributed across many subcortical regions. These long-range inhibitory neurons are exclusively GABAergic and do not co-release excitatory glutamate. Furthermore, activation of the LRG terminals in the nucleus accumbens resulted in acute avoidance behaviors, demonstrating that these neurons may be involved in influencing motivated behaviors. Our third study investigates roles for prefrontal VIP neurons in local and distributed anxiety networks. Fiber photometry of VIP neurons reflect increased activity in anxiogenic regions of the elevated plus maze (EPM) and inhibition of these neurons resulted in increased open arm exploration. Multi-site recordings of local field potentials showed that theta synchrony between ventral hippocampus (vHPC) and PFC was disrupted when prefrontal VIP neurons were inhibited. Finally, using combined optogenetic-endoscope imaging, we found that VIP neurons control the gain of anxiety-generated changes in prefrontal microcircuit activity. These findings highlight the specialized natures of interneuron subtypes in the mammalian brain, and provide evidence for how their microcircuit functions subserve complex behaviors.