The dynamics of disordered dialogue: Prefrontal, hippocampal and thalamic miscommunication underlying working memory deficits in schizophrenia

Abstract

The prefrontal cortex is central to the orchestrated brain network communication that gives rise to working memory and other cognitive functions. Accordingly, working memory deficits in schizophrenia are increasingly thought to derive from prefrontal cortex dysfunction coupled with broader network disconnectivity. How the prefrontal cortex dynamically communicates with its distal network partners to support working memory and how this communication is disrupted in individuals with schizophrenia remain unclear. Here we review recent evidence that prefrontal cortex communication with the hippocampus and thalamus is essential for normal spatial working memory, and that miscommunication between these structures underlies spatial working memory deficits in schizophrenia. We focus on studies using normal rodents and rodent models designed to probe schizophrenia-related pathology to assess the dynamics of neural interaction between these brain regions. We also highlight recent preclinical work parsing roles for long-range prefrontal cortex connections with the hippocampus and thalamus in normal and disordered spatial working memory. Finally, we discuss how emerging rodent endophenotypes of hippocampal- and thalamo-prefrontal cortex dynamics in spatial working memory could translate into richer understanding of the neural bases of cognitive function and dysfunction in humans.

Dysregulation of Midbrain Dopamine System and the Pathophysiology of Schizophrenia

“…Recent rodent studies have similarly indicated circuit abnormalities underlying and resulting from thalamic dysfunction (108). The thalamus is composed of multiple nuclei, each with their distinct afferent and efferent projections (109).…”

Developmental decrease of entorhinal gate disrupts prefrontal-hippocampal communication in immune-challenged DISC1 knockdown mice

“…Abnormal prefrontal-hippocampal coupling during the tasks has been described in schizophrenia patients 4,6 . It relates not only to local alterations at microscopic and macroscopic scales in both areas 7 but also to connectivity dysfunction within large-scale networks 8 . In particular, the interactions between HP and entorhinal cortex, which tightly communicate with each other along reciprocal pathways 9 , have been tackled in clinical and neuropathological investigations 10,11,12,13 .…”

Longitudinal tracing of neurochemical metabolic disorders in working memory neural circuit and optogenetics modulation in rats with vascular cognitive impairment

“…Moreover, during the memory maintenance phase, the direction of information ow is from the hippocampus to mPFC, while during the memory retrieval phase, the direction is from the mPFC to hippocampus (Dolleman-van et al, 2019;Eichenbaum, 2017). In recent years, studies have demonstrated that the mPFC exist mutual connectivity and communication with the hippocampus and mediodorsal thalamus and are essential for maintaining working memory (Bolkan et al, 2017;Kupferschmidt and Gordon, 2018;Parnaudeau et al, 2018;Schmitt et al, 2017). In the mediodorsal thalamus, there are glutamatergic thalamocortical neurons and GABAergic interneurons (Kuroda et al, 1998;Tiwari et al, 2013) that receive projection from mPFC neurons and then drive mPFC activity to integrate signals for adaptive goal-directed behavior (Miller et al, 2017).…”