Prelimbic cortex drives discrimination of non-aversion via amygdala somatostatin interneurons.

The amygdala and prelimbic cortex (PL) communicate during fear discrimination retrieval, but how they coordinate discrimination of a non-threatening stimulus is unknown. Here, we show that somatostatin (SOM) interneurons in the basolateral amygdala (BLA) become active specifically during learned non-threatening cues and desynchronize cell firing by blocking phase reset of theta oscillations during the safe cue. Furthermore, we show that SOM activation and desynchronization of the BLA is PL-dependent and promotes discrimination of non-threat. Thus, fear discrimination engages PL-dependent coordination of BLA SOM responses to non-threatening stimuli.

Publisher Correction: Thalamic projections sustain prefrontal activity during working memory maintenance.

In the version of this article initially published, the title of ref. 45 was given as "Sustaining cortical representations by a content-free thalamic amplifier." The correct title is "Thalamic amplification of cortical connectivity sustains attentional control." The error has been corrected in the HTML and PDF versions of the article.

Hippocampal-prefrontal theta-gamma coupling during performance of a spatial working memory task.

Cross-frequency coupling supports the organization of brain rhythms and is present during a range of cognitive functions. However, little is known about whether and how long-range cross-frequency coupling across distant brain regions subserves working memory. Here we report that theta-slow gamma coupling between the hippocampus and medial prefrontal cortex (mPFC) is augmented in a genetic mouse model of cognitive dysfunction. This increased cross-frequency coupling is observed specifically when the mice successfully perform a spatial working memory task. In wild-type mice, increasing task difficulty by introducing a long delay or by optogenetically interfering with encoding, also increases theta-gamma coupling during correct trials. Finally, epochs of high hippocampal theta-prefrontal slow gamma coupling are associated with increased synchronization of neurons within the mPFC. These findings suggest that enhancement of theta-slow gamma coupling reflects a compensatory mechanism to maintain spatial working memory performance in the setting of increased difficulty.

Thalamic projections sustain prefrontal activity during working memory maintenance.

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. Using pathway-specific inhibition, we found directional interactions between mouse 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 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.

Direct Ventral Hippocampal-Prefrontal Input Is Required for Anxiety-Related Neural Activity and Behavior.

The ventral hippocampus (vHPC), medial prefrontal cortex (mPFC), and basolateral amygdala (BLA) are each required for the expression of anxiety-like behavior. Yet the role of each individual element of the circuit is unclear. The projection from the vHPC to the mPFC has been implicated in anxiety-related neural synchrony and spatial representations of aversion. The role of this projection was examined using multi-site neural recordings combined with optogenetic terminal inhibition. Inhibition of vHPC input to the mPFC disrupted anxiety and mPFC representations of aversion, and reduced theta synchrony in a pathway-, frequency- and task-specific manner. Moreover, bilateral, but not unilateral, inhibition altered physiological correlates of anxiety in the BLA, mimicking a safety-like state. These results reveal a specific role for the vHPC-mPFC projection in anxiety-related behavior and the spatial representation of aversive information within the mPFC.

Molecular substrates of altered axonal growth and brain connectivity in a mouse model of schizophrenia.

22q11.2 deletion carriers show specific cognitive deficits, and ∼30% of them develop schizophrenia. One of the disrupted genes is ZDHHC8, which encodes for a palmitoyltransferase. We show that Zdhhc8-deficient mice have reduced palmitoylation of proteins that regulate axonal growth and branching. Analysis of axonal projections of pyramidal neurons from both Zdhhc8-deficient and Df(16)A(+/-) mice, which model the 22q11.2 deletion, revealed deficits in axonal growth and terminal arborization, which can be prevented by reintroduction of active ZDHHC8 protein. Impaired terminal arborization is accompanied by a reduction in the strength of synaptic connections and altered functional connectivity and working memory. The effect of ZDHHC8 is mediated in part via Cdc42-dependent modulation of Akt/Gsk3ß signaling at the tip of the axon and can be reversed by pharmacologically decreasing Gsk3ß activity during postnatal brain development. Our findings provide valuable mechanistic insights into the cognitive and psychiatric symptoms associated with a schizophrenia-predisposing mutation.

Synchrony in schizophrenia: a window into circuit-level pathophysiology.

As a complex neuropsychiatric disease with both hereditary and environmental components, schizophrenia must be understood across multiple biological scales, from genes through cells and circuits to behaviors. The key to evaluating candidate explanatory models, therefore, is to establish causal links between disease-related phenomena observed across these scales. To this end, there has been a resurgence of interest in the circuit-level pathophysiology of schizophrenia, which has the potential to link molecular and cellular data from risk factor and post-mortem studies with the behavioral phenomena that plague patients. The demonstration that patients with schizophrenia frequently have deficits in neuronal synchrony, including deficits in local oscillations and long-range functional connectivity, offers a promising opportunity to forge such links across scales.

Disruption of component processes of spatial working memory by electroconvulsive shock but not magnetic seizure therapy.

Self-ordered spatial working memory measures provide important information regarding underlying cognitive strategies, such as stereotypy. This strategy is based on repetitive sequential selection of a spatial pattern once a correct sequence has been identified. We previously reported that electroconvulsive shock (ECS) but not magnetic seizure therapy (MST) impaired performance on a spatial working memory task in a preclinical model. Here we tested the hypothesis that ECS disrupted stereotyped patterns in the selection of spatial stimuli. In a within-subject study design, we assessed the effects of ECS, MST, and sham on stereotypy and reaction time in a preclinical model. Stereotypy was assessed by the correlation of actual and predicted response patterns of spatial stimuli. Predicted patterns were based on performance during baseline sessions. ECS resulted in lower correlations between predicted and actual responses to spatial stimuli in two of the three subjects, and it also disrupted stereotypy. For one subject, there was change in the predictability of the spatial locus of responses between experimental conditions. For all three subjects, reaction time was significantly longer in ECS, relative to MST and sham. This is the first study to examine the effect of ECS, and to contrast the effects of ECS and MST, on spatial working memory component processes. Our preliminary findings show that ECS, but not MST decreased stereotypy and increased reaction time. This line of investigation may have significant implications in our understanding cognitive component processes of memory function and impairment.