Temporal information in the anterior cingulate cortex relates to accumulated experiences.

Anterior cingulate cortex (ACC) activity is important for operations that require the ability to integrate multiple experiences over time, such as rule learning, cognitive flexibility, working memory, and long-term memory recall. To shed light on this, we analyzed neuronal activity while rats repeated the same behaviors during hour-long sessions to investigate how activity changed over time. We recorded neuronal ensembles as rats performed a decision-free operant task with varying reward likelihoods at three different response ports (n = 5). Neuronal state space analysis revealed that each repetition of a behavior was distinct, with more recent behaviors more similar than those further apart in time. ACC activity was dominated by a slow, gradual change in low-dimensional representations of neural state space aligning with the pace of behavior. Temporal progression, or drift, was apparent on the top principal component for every session and was driven by the accumulation of experiences and not an internal clock. Notably, these signals were consistent across subjects, allowing us to accurately predict trial numbers based on a model trained on data from a different animal. We observed that non-continuous ramping firing rates over extended durations (tens of minutes) drove the low-dimensional ensemble representations. 40% of ACC neurons' firing ramped over a range of trial lengths and combinations of shorter duration ramping neurons created ensembles that tracked longer durations. These findings provide valuable insights into how the ACC, at an ensemble level, conveys temporal information by reflecting the accumulation of experiences over extended periods.

Reduction in GABAB on glia induce Alzheimer's disease related changes.

Alzheimer's Disease (AD) is a neurodegenerative disorder characterized by beta-amyloid plaques (Aß), neurofibrillary tangles (NFT), and neuroinflammation. Data have demonstrated that neuroinflammation contributes to Aß and NFT onset and progression, indicating inflammation and glial signaling is vital to understanding AD. A previous investigation demonstrated a significant decrease of the GABAB receptor (GABABR) in APP/PS1 mice (Salazar et al., 2021). To determine if changes in GABABR restricted to glia serve a role in AD, we developed a mouse model with a reduction of GABABR restricted to macrophages, GAB/CX3ert. This model exhibits changes in gene expression and electrophysiological alterations similar to amyloid mouse models of AD. Crossing the GAB/CX3ert mouse with APP/PS1 resulted in significant increases in Aß pathology. Our data demonstrates that decreased GABABR on macrophages leads to several changes observed in AD mouse models, as well as exacerbation of AD pathology when crossed with existing models. These data suggest a novel mechanism in AD pathogenesis.

Altered theta rhythm and hippocampal-cortical interactions underlie working memory deficits in a hyperglycemia risk factor model of Alzheimer's disease.

Diabetes mellitus is a metabolic disease associated with dysregulated glucose and insulin levels and an increased risk of developing Alzheimer's disease (AD) later in life. It is thought that chronic hyperglycemia leads to neuroinflammation and tau hyperphosphorylation in the hippocampus leading to cognitive decline, but effects on hippocampal network activity are unknown. A sustained hyperglycemic state was induced in otherwise healthy animals and subjects were then tested on a spatial delayed alternation task while recording from the hippocampus and anterior cingulate cortex (ACC). Hyperglycemic animals performed worse on long delay trials and had multiple electrophysiological differences throughout the task. We found increased delta power and decreased theta power in the hippocampus, which led to altered theta/delta ratios at the end of the delay period. Cross frequency coupling was significantly higher in multiple bands and delay period hippocampus-ACC theta coherence was elevated, revealing hypersynchrony. The highest coherence values appeared long delays on error trials for STZ animals, the opposite of what was observed in controls, where lower delay period coherence was associated with errors. Consistent with previous investigations, we found increases in phosphorylated tau in STZ animals' hippocampus and cortex, which might account for the observed oscillatory and cognitive changes.

Spatial Cognition: Prenatal Alcohol Exposure and the Memory Puzzle.

We navigate through space using the coordinated activity of spatially sensitive cells in the hippocampus. A new study shows that moderate prenatal alcohol exposure alters multiple features of hippocampal spatial responses, leading to inflexible and less precise representations of our surroundings.

ACC Theta Improves Hippocampal Contextual Processing during Remote Recall.

Consolidation studies show that, over time, memory recall becomes independent of the medial temporal lobes. Multiple lines of research show that the medial frontal cortex, including the anterior cingulate cortex (ACC), is involved with contextual information processing and remote recall. We hypothesize that interactions between the ACC and hippocampal area CA1 will change as memories became more remote. Animals are re-exposed to multiple environments at different retention intervals. During remote recall, ACC-CA1 theta coherence increases, with the ACC leading area CA1. ACC theta regulates unit spike timing, gamma oscillations, and ensemble and single-neuron information coding in CA1. Over the course of consolidation, the strength and prevalence of ACC theta modulation grow, leading to richer environmental context representations in CA1. These data are consistent with the transference of contextual memory dependence to the ACC and indicate that remote memories are retrieved via ACC-driven oscillatory coupling with CA1.

Integrating Spatial Working Memory and Remote Memory: Interactions between the Medial Prefrontal Cortex and Hippocampus.

In recent years, two separate research streams have focused on information sharing between the medial prefrontal cortex (mPFC) and hippocampus (HC). Research into spatial working memory has shown that successful execution of many types of behaviors requires synchronous activity in the theta range between the mPFC and HC, whereas studies of memory consolidation have shown that shifts in area dependency may be temporally modulated. While the nature of information that is being communicated is still unclear, spatial working memory and remote memory recall is reliant on interactions between these two areas. This review will present recent evidence that shows that these two processes are not as separate as they first appeared. We will also present a novel conceptualization of the nature of the medial prefrontal representation and how this might help explain this area's role in spatial working memory and remote memory recall.