Title: Thalamo-prefrontal substrates regulating cognitive behaviors in mice
Description: A hallmark of intelligence in humans and other animals is the ability to engage in complex behaviors geared towards achieving far-removed goals. Such behavior relies on a set of diverse and sophisticated mental processes that are collectively referred to as cognitive or executive in nature. The prefrontal cortex (PFC) has long been considered the primary neural locus for such processes. From humans down to rodents, damage to the PFC has been shown to impair cognition and executive function. In neuropsychiatric disorders such as schizophrenia, dysfunction of the PFC has been strongly linked to cognitive dysfunction. PFC functioning however, necessarily relies on interactions within and between networks of interconnected neurons. Across species, the PFC has been anatomically defined as the region of cortex reciprocally connected with the mediodorsal thalamus (MD), a definition that suggests PFC functioning cannot be divorced from that of its main thalamic counterpart. Indeed, an increasing number of studies have demonstrated the involvement of MD in cognitive behaviors.

Schizophrenia patients performing cognitive tasks also exhibit decreased MD activity, with growing evidence for decreased functional connectivity with the PFC. The studies presented here seek to build on this literature using the mouse as a model organism. Taking advantage of recent tools for temporally- and spatially-restricted manipulations of neural activity we show that a relatively mild and reversible decrease in MD activity is capable of impairing two cognitive behaviors classically shown to be PFC-dependent – behavioral flexibility and working memory. Simultaneously recording MD and PFC activity while mice perform a spatial working memory task, we show task modulations of synchronous MD-PFC activity that are disrupted by a primary decrease in MD activity. Following up on this finding using pathway-specific manipulations of MD-to-PFC and PFC-to-MD neural connections, we provide behavioral and neurophysiological evidence that these circuits serve as distinct neural substrates for working memory maintenance and retrieval.

Together, these findings provide causal evidence in support of an association between thalamo-prefrontal dysfunction and cognitive impairment, and may enable the development of more selective therapeutic strategies for cognitive disorders such as schizophrenia.