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

Changes in Hippocampal-Anterior Cingulate Cortex Interactions During Remote Memory Recall

Spatial memory is an important cognitive process that relies on extensive neural networks throughout the brain. The hippocampus (HC) is important for the formation of these memories but over time, in a process referred to as consolidation, recall becomes increasingly reliant on other brain areas. The anterior cingulate cortex (ACC), a region within the medial prefrontal cortex, is important for spatial learning, spatial working memory, and remote memory recall, but the mechanisms underlying recall processes are still unknown. To better understand the role of the ACC and HC during memory recall, we introduced rodents into a series of spatially and texturally unique environments at differing delay periods (day 1 (learning), day 11 (recent), and day 18 (remote)) while simultaneously recording local field potentials (LFPs) from both areas. We found significant increases in theta band coherence between ipsilateral ACC and HC LFPs during remote memory recall but not recent memory recall. In addition to these changes, directional analysis revealed a reversal in signal initiation, such that during the learning and recent recall condition, hippocampal theta oscillations led ACC theta oscillations. However, during the remote recall condition, the direction changed, and ACC theta led hippocampal theta activity. This experiment provides evidence of time-dependent changes in ACC – hippocampal network interactions, and illustrates a possible mechanism that describes how the ACC mediates recall of remote spatial memories

Continuous Theta Rhythm During Spatial Working Memory Task in Rodent Models of Streptozotocin-induced Type 2 Diabetes

Alzheimer’s disease is a neurodegenerative disorder altering memory loss thought to be due to neuropathological symptoms such as the buildup of beta amyloid plaques (Ab) and neurofibrillary tangles (NFT). The etiology of Alzheimer’s is still unknown; however, potential risk factors such as diabetes may lead to its development. The most common form of diabetes is type 2 diabetes known for persistent insulin resistance leading to a state of hyperglycemia. Insulin resistance has been shown to affect cognitive abilities such as learning, memory and also alters synaptic plasticity. Neural connections between the hippocampus (HC) and anterior cingulate cortex (ACC) are known to be very important for learning and memory and are highly plastic, making them an intriguing target that could be altered by hyperglycemia. We hypothesize that hyperglycemic rodents will exhibit spatial memory deficits that may be associated with cognitively linked interactions between the HC and ACC. Minimal doses of streptozotocin (STZ), which is toxic to insulin producing beta cells, were given for 9-10 weeks. Using a spatial working memory task known as delayed alternation we found significant differences between control and experimental rats in working memory accuracy. This task places strong working memory demands on subjects which may be compromised by a hyperglycemic state. We measured EEG recordings from the HC and ACC during task performance and found that hyperglycemic rats had nearly continuous theta rhythm during the 30-minute session. Control rats however, displayed normal transitions between theta and lower frequency delta. Neural connectivity may be altered due to a change in frequency activity between the HC and ACC due to diabetes which is a risk factor in the development of AD impairments. These results show that hyperglycemia leads to changes along the circuit critical for learning and memory

Construction and Assembly of a Hyperdrive Recording Implant

The ability to record neural activity from multiple brain areas is crucial for the understanding of how different areas of the brain function or interact. This poster will cover instructions on how to construct and assemble a hyperdrive recording implant that bilaterally targets the ACC and the hippocampus. Intriguingly, the design of the hyperdrive recording implant is flexible and can be constructed to target other brain areas. The implant consists of 32 twisted bundles of tetrodes with a total of 128 individual recording wires which are controlled by movable ‘drivers’ (Gray et al., 1995; McNaughton et al., 1983). All 128 recording wires are then connected to an electrode interface board that takes information from the brain and transfers it to online available open-source acquisition software platform running. Using this implant with targeted tetrodes, we are able to look at the neuronal waveforms of individual neurons or the population-level responses in specific brain areas

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

Diabetes Mellitus Affects Working Memory

Alzheimer’s disease (AD) degrades the brain’s ability to remember, think, and carry out tasks. The exact cause is not known, but several risk factors have been identified, including diabetes mellitus (DM). DM causes elevated blood sugar levels due to reduced insulin production in the pancreas. The linkage between elevated glucose levels and the behavioral impairments are not fully understood, which was the focus of this study. Rats were trained to alternate directions in a maze to receive a reward on consecutive trials. After training, five rats were injected with streptozotocin (STZ), which induces hyperglycemia by injuring pancreatic beta cells. Three control animals received benign vehicle injections. All eight rats then underwent implant surgery and received an implant with 128 recording probes attached to an electronic interface board. The recording electrodes targeted the hippocampus and the anterior cingulate cortex (ACC), which are both associated with learning and memory processes. We found that STZ rats had reduced accuracy after long delay periods compared to the control rats. During task performance, there was a decrease in the power of theta activity and an increase in delta activity moments before starting a new trial. This was the opposite of control animals, who before starting new trials had higher theta power and less delta power as they focused. These findings imply that the STZ rats were impaired on longer delay periods. These findings are like reports from animal models of AD and may help explain why DM is a risk factor for AD

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. To investigate the effects of chronic hyperglycemia on hippocampal network activity Wirt et al induced sustained hyperglycemia in rats and tested them in a spatial delayed alternation task while recording from the hippocampus and anterior cingulate cortex. They demonstrated that hyperglycemia impaired task performance and altered theta rhythm as well as increasing tau phosphorylation, which suggest there is potentially a direct link between chronic hyperglycemia and Alzheimer’s disease

The Effects of Altered GABAergic Signaling in Microglia on Hippocampal-cortical Network Activity and Remote Recall

Memory acquisition and encoding are modulated by neural network activity between the hippocampus (HPC) and prefrontal cortex (PFC). Research has shown that neuroimmune defense cells, glia, interact with neurons in both brain regions. However, little is known about glial-neuronal interactions, and how these interactions affect memory network activity and in turn, memory recall. Memory network activity involves a host of cellular excitation and inhibition. The primary neurotransmitter involved in inhibition is γ-aminobutyric acid (GABA), and receptors for this neurotransmitter can also be found on microglia. To better understand glial-neuronal interactions between the HPC and PFC, we utilized a mouse model (GABABFlox) with a knockdown of GABAB receptors on microglia, to alter microglial activity. Our lab utilizes electrophysiological recordings of neuronal activity related to learning and memory in the HPC and PFC. Mice were implanted with 64-channel implants to record from single cells and local field potentials (LFPs) while completing a conditioned place preference task to measure remote recall. Results showed that GABABFlox mice had remote recall (18days) deficits but intact recent recall (1day). We also found that GABABFlox mice had changes in multiple electrophysiological signals associated with memory processing, including: decreased gamma power in the HPC, impairments in theta-gamma comodulation in the cortex, theta and delta hypersynchrony between the HPC and cortex, and fewer sharp-wave ripples in the HPC. These findings suggest that GABAergic signaling on microglia may facilitate neural network systems involved in memory formation and recall, and that alterations in microglia may impair functions necessary for memory formation.https://digitalscholarship.unlv.edu/durep_posters/1066/thumbnail.jp

Reduction in GABAB on glia induce Alzheimer\u27s disease related changes.

Alzheimer’s Disease (AD) is a neurodegenerative disorder characterized by beta-amyloid plaques (Aβ), neuro- fibrillary tangles (NFT), and neuroinflammation. Data have demonstrated that neuroinflammation contributes to Aβ 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 Aβ pathology. Our data demonstrates that decreased GABABR on macrophages leads to several changes observed in AD mouse models, as well as exacer- bation of AD pathology when crossed with existing models. These data suggest a novel mechanism in AD pathogenesis