Thalamic projections sustain prefrontal activity during working memory maintenance

Abstract

The mediodorsal thalamus (MD) shares reciprocal connectivity with the prefrontal cortex (PFC) and decreased MD-PFC connectivity is observed in schizophrenia patients. Patients also display cognitive deficits including impairments in working memory, but a mechanistic link between thalamo-prefrontal circuit function and working memory is missing. Here, using pathway-specific inhibition we found directional interactions between MD and medial PFC (mPFC), with MD-to-mPFC supporting working memory maintenance and mPFC-to-MD supporting subsequent choice. We further identify mPFC neurons that display elevated spiking during the delay, a feature that was absent on error trials and required MD inputs for sustained maintenance. Strikingly, delay-tuned neurons had minimal overlap with spatially-tuned neurons and each mPFC population exhibited mutually exclusive dependence on MD and hippocampal inputs. These findings indicate a role for the MD in sustaining prefrontal activity during working memory maintenance. Consistent with this idea we found that enhancing MD excitability was sufficient to enhance task performance.

Temporal and spatial context in the mind and brain

“…These predictions resemble the properties of hippocampal “time cells” that fire sequentially during a circumscribed period within a delay period [60, 49]. Consistent with the hypothesis that the compressed representation of the past is accessed in many different forms of memory, time cells are not only observed in the hippocampus [51], but also the entorhinal cortex [52], striatum [54, 61], and medial PFC [53, 62]. Notably, in all of these studies, time cells show a characteristic compression as qualitatively predicted by theory (Fig.…”

Thalamic Control of Cognition and Social Behavior Via Regulation of Gamma-Aminobutyric Acidergic Signaling and Excitation/Inhibition Balance in the Medial Prefrontal Cortex

“…We predict that high levels of inhibition suppress the activity of functional units of neurons or microcolumns representing distracting information. In concert with the appropriate patterns of excitation, dynamic regulation of these two opposing forces likely support the maintenance of delay-dependent neuronal activity and sustain rule representations in the mPFC as was demonstrated recently (2, 4). Enabling excitatory reverberation to be preferentially sustained within microcolumns representing the correct information could allow the mPFC to optimally process incoming task-related information that can be fed forward to drive the appropriate behavior (Fig 8).…”

“…A prime opportunity to advance our understanding of mPFC function is by focusing on the mechanisms of communication with one of its primary gateways, the mediodorsal thalamus (MD). However, despite recent progress (2–4), our grasp on the nature of the interaction between these two structures remains limited.…”

A neural microcircuit model for a scalable scale‐invariant representation of time

“…(b) After Tiganj et al (). (c) After Bolkan et al (). (d) After MacDonald et al () [Color figure can be viewed at wileyonlinelibrary.com]…”

“…Time cells were observed when an animal is performing delayed match to sample (MacDonald, Lepage, Eden, & Eichenbaum, ), delayed match to category (Tiganj, Cromer, Roy, Miller, & Howard, ), spatial alternation (Salz et al, ), or temporal discrimination tasks (Tiganj, Kim, Jung, & Howard, ). Time cells have been found in various parts of the brain including the hippocampus (MacDonald et al, ; Salz et al, ), prefrontal cortex (PFC) (Bolkan et al, ; Jin, Fujii, & Graybiel, ; Tiganj et al, ) and striatum (Adler et al, ; Akhlaghpour et al, ; Mello, Soares, & Paton, ). A recent study suggests that neurons in the amygdala are sequentially activated during the intertrial interval of a conditioning task (Taub, Stolero, Livneh, Shohat, & Paz, ).…”