#parvalbumin

Dopamine is required for working memory, but how it modulates the large-scale cortex is unknown. Here, we report that dopamine receptor density per neuron, measured by autoradiography, displays a macroscopic gradient along the macaque cortical hierarchy. This gradient is incorporated in a connectome-based large-scale cortex model endowed with multiple neuron types. The model captures an inverted U-shaped dependence of working memory on dopamine and spatial patterns of persistent activity observed in over 90 experimental studies. Moreover, we show that dopamine is crucial for filtering out irrelevant stimuli by enhancing inhibition from dendrite-targeting interneurons. Our model revealed that an activity-silent memory trace can be realized by facilitation of inter-areal connections and that adjusting cortical dopamine induces a switch from this internal memory state to distributed persistent activity. Our work represents a cross-level understanding from molecules and cell types to recurrent circuit dynamics underlying a core cognitive function distributed across the primate cortex.

image i used for my stickers!

When mice are engineered to lack the mGluR5 receptor in parvalbumin cells (right), they have fewer inhibitory (red) connections controlling the activity of excitatory neurons. Image: Courtesy of the Salk Institute for Biological Studies

Linking specific neuronal types to well-defined behaviors has proved extremely difficult. “There’s a big gap in our knowledge between our understanding of neuron types in terms of their physical location and their place in any given neural circuit, and what these neurons actually do during behavior,” says Kepecs. Part of the problem is the technical challenge of doing these studies in live, freely behaving mice. Key to solving that problem is a mouse model developed in the laboratory of CSHL Professor Z. Josh Huang. The mouse has a genetic modification that allows investigators to target a specific population of neurons with any protein of interest. Kepecs’ group, led by postdocs Duda Kvitsiani and Sachin Ranade, used this mouse to label specific neuron types in the ACC with a light-activated protein – a technique known as optogenetic tagging. Whenever they shone light onto the brains of the mice they were recording from, only the tagged PV and SOM neurons responded promptly with a ‘spike’ in their activity, enabling the researchers to pick them out from the vast diversity of cellular responses seen at any given moment. The team recorded neural activity in the ACC of these mice while they engaged in foraging behavior. They discovered that the PV and SOM inhibitory neurons responded around the time of the foraging decisions -- in other words whether to stay and drink or go and explore elsewhere. Specifically, when the mice entered an area where they could collect a water reward, SOM inhibitory neurons shut down and entered a period of low-level activity, thereby opening a ‘gate’ for information to flow in to ACC. When the mice decided to leave that area and look elsewhere, PV inhibitory neurons fired and abruptly reset cell activity. “The brain is complex and continuously active, so it makes sense that these two types of inhibitory interneurons define the boundaries of a behavior such as foraging, opening and then closing the ‘gate’ within a particular neural circuit through changes in their activity,” says Kepecs. This is an important advance, addressing a problem in behavioral neuroscience that scientists call “the cortical response zoo.” When researchers record neural activity in cortex during behavior, and they don’t know which type of neurons they are recording from, a bewildering array of responses is seen. This greatly complicates the task of interpretation. Hence the significance of the Kepecs team’s results, for the first time showing that specific cortical neuron types can be linked to specific aspects of behavior. “We think about the brain and behavior in terms of levels; what the cell types are and the circuits or networks they form; which regions of the brain they are in; and what behavior is modulated by them,” explains Kepecs. “By observing that the activity of specific cell types in the prefrontal cortex is correlated with a behavioral period, we have identified a link between these levels.” “Distinct behavioural and network correlates of two interneuron types in prefrontal cortex” is published online in Nature on May 26, 2013.  The authors are: D. Kvitsiani, S. Ranade, B. Hangya, H. Taniguchi, Z. J. Huang, A. Kepecs. The paper can be obtained online at doi:10.1038/nature12176.