Cell-type-specific cholinergic control of granular retrosplenial cortex with implications for angular velocity coding across brain states.

Cholinergic receptor activation enables the persistent firing of cortical pyramidal neurons, providing a key cellular basis for theories of spatial navigation involving working memory, path integration, and head direction encoding. The granular retrosplenial cortex (RSG) is important for spatially-guided behaviors, but how acetylcholine impacts RSG neurons is unknown. Here, we show that a transcriptomically, morphologically, and biophysically distinct RSG cell-type - the low-rheobase (LR) neuron - has a very distinct expression profile of cholinergic muscarinic receptors compared to all other neighboring excitatory neuronal subtypes. LR neurons do not fire persistently in response to cholinergic agonists, in stark contrast to all other principal neuronal subtypes examined within the RSG and across midline cortex. This lack of persistence allows LR neuron models to rapidly compute angular head velocity (AHV), independent of cholinergic changes seen during navigation. Thus, LR neurons can consistently compute AHV across brain states, highlighting the specialized RSG neural codes supporting navigation.

Cellular rules underlying psychedelic control of prefrontal pyramidal neurons.

Classical psychedelic drugs are thought to increase excitability of pyramidal cells in prefrontal cortex via activation of serotonin 2A receptors (5-HT2ARs). Here, we instead find that multiple classes of psychedelics dose-dependently suppress intrinsic excitability of pyramidal neurons, and that extracellular delivery of psychedelics decreases excitability significantly more than intracellular delivery. A previously unknown mechanism underlies this psychedelic drug action: enhancement of ubiquitously expressed potassium "M-current" channels that is independent of 5-HT2R activation. Using machine-learning-based data assimilation models, we show that M-current activation interacts with previously described mechanisms to dramatically reduce intrinsic excitability and shorten working memory timespan. Thus, psychedelic drugs suppress intrinsic excitability by modulating ion channels that are expressed throughout the brain, potentially triggering homeostatic adjustments that can contribute to widespread therapeutic benefits.

Thalamus and claustrum control parallel layer 1 circuits in retrosplenial cortex.

The granular retrosplenial cortex (RSG) is critical for both spatial and non-spatial behaviors, but the underlying neural codes remain poorly understood. Here, we use optogenetic circuit mapping in mice to reveal a double dissociation that allows parallel circuits in superficial RSG to process disparate inputs. The anterior thalamus and dorsal subiculum, sources of spatial information, strongly and selectively recruit small low-rheobase (LR) pyramidal cells in RSG. In contrast, neighboring regular-spiking (RS) cells are preferentially controlled by claustral and anterior cingulate inputs, sources of mostly non-spatial information. Precise sublaminar axonal and dendritic arborization within RSG layer 1, in particular, permits this parallel processing. Observed thalamocortical synaptic dynamics enable computational models of LR neurons to compute the speed of head rotation, despite receiving head direction inputs that do not explicitly encode speed. Thus, parallel input streams identify a distinct principal neuronal subtype ideally positioned to support spatial orientation computations in the RSG.

Sitting in your car, about to drive home after a long day at work, you realize you have no idea which way to go: you recognize where you are right now, and you remember the name of the street your house is on, but you cannot figure out how to get there. This spatial disorientation happens to people with damage to a brain region called the retrosplenial cortex, whose role and inner workings remain poorly understood. Recent evidence has shown that this area contains 'low-rheobase' neurons which are not seen anywhere else in the brain, but what do these neurons do? Brennan, Jedrasiak-Cape, Kailasa et al. decided to explore the role of these neurons, focusing on the brain regions they are connected to. Experiments were conducted in mice using optogenetics, a technique that activates neurons using pulses of light. This revealed that brain areas involved in processing information about direction and position preferentially communicate with low-rheobase neurons rather than with nearby, more standard neurons in the retrosplenial cortex. The way these spatial signals are sent to the low-rheobase neurons allows these cells to 'calculate' how fast a mouse is turning its head using only information about which direction the mouse is facing. Essentially, this neuron can turn directional compass-like signals into a gyroscope signal that can track both direction and speed of head movement. These unique neurons may therefore be ideally suited to combine information about direction and space, suggesting that they may have evolved specifically to support spatial navigation. Individuals with Alzheimer's disease show exactly the same type of spatial disorientation as individuals with direct damage to the retrosplenial cortex. This region is also one of the first to show altered activity in Alzheimer's disease. Exploring whether these unique retrosplenial neurons and their communication patterns are altered in Alzheimer's disease models could help to understand and potentially treat this debilitating condition.

Hyperexcitable Neurons Enable Precise and Persistent Information Encoding in the Superficial Retrosplenial Cortex.

The retrosplenial cortex (RSC) is essential for memory and navigation, but the neural codes underlying these functions remain largely unknown. Here, we show that the most prominent cell type in layers 2/3 (L2/3) of the mouse granular RSC is a hyperexcitable, small pyramidal cell. These cells have a low rheobase (LR), high input resistance, lack of spike frequency adaptation, and spike widths intermediate to those of neighboring fast-spiking (FS) inhibitory neurons and regular-spiking (RS) excitatory neurons. LR cells are excitatory but rarely synapse onto neighboring neurons. Instead, L2/3 is a feedforward, not feedback, inhibition-dominated network with dense connectivity between FS cells and from FS to LR neurons. Biophysical models of LR but not RS cells precisely and continuously encode sustained input from afferent postsubicular head-direction cells. Thus, the distinct intrinsic properties of LR neurons can support both the precision and persistence necessary to encode information over multiple timescales in the RSC.

Circadian and Brain State Modulation of Network Hyperexcitability in Alzheimer's Disease.

Network hyperexcitability is a feature of Alzheimer' disease (AD) as well as numerous transgenic mouse models of AD. While hyperexcitability in AD patients and AD animal models share certain features, the mechanistic overlap remains to be established. We aimed to identify features of network hyperexcitability in AD models that can be related to epileptiform activity signatures in AD patients. We studied network hyperexcitability in mice expressing amyloid precursor protein (APP) with mutations that cause familial AD, and compared a transgenic model that overexpresses human APP (hAPP) (J20), to a knock-in model expressing APP at physiological levels (APPNL/F). We recorded continuous long-term electrocorticogram (ECoG) activity from mice, and studied modulation by circadian cycle, behavioral, and brain state. We report that while J20s exhibit frequent interictal spikes (IISs), APPNL/F mice do not. In J20 mice, IISs were most prevalent during daylight hours and the circadian modulation was associated with sleep. Further analysis of brain state revealed that IIS in J20s are associated with features of rapid eye movement (REM) sleep. We found no evidence of cholinergic changes that may contribute to IIS-circadian coupling in J20s. In contrast to J20s, intracranial recordings capturing IIS in AD patients demonstrated frequent IIS in non-REM (NREM) sleep. The salient differences in sleep-stage coupling of IIS in APP overexpressing mice and AD patients suggests that different mechanisms may underlie network hyperexcitability in mice and humans. We posit that sleep-stage coupling of IIS should be an important consideration in identifying mouse AD models that most closely recapitulate network hyperexcitability in human AD.