Neural manifold analysis of brain circuit dynamics in health and disease.

Recent developments in experimental neuroscience make it possible to simultaneously record the activity of thousands of neurons. However, the development of analysis approaches for such large-scale neural recordings have been slower than those applicable to single-cell experiments. One approach that has gained recent popularity is neural manifold learning. This approach takes advantage of the fact that often, even though neural datasets may be very high dimensional, the dynamics of neural activity tends to traverse a much lower-dimensional space. The topological structures formed by these low-dimensional neural subspaces are referred to as "neural manifolds", and may potentially provide insight linking neural circuit dynamics with cognitive function and behavioral performance. In this paper we review a number of linear and non-linear approaches to neural manifold learning, including principal component analysis (PCA), multi-dimensional scaling (MDS), Isomap, locally linear embedding (LLE), Laplacian eigenmaps (LEM), t-SNE, and uniform manifold approximation and projection (UMAP). We outline these methods under a common mathematical nomenclature, and compare their advantages and disadvantages with respect to their use for neural data analysis. We apply them to a number of datasets from published literature, comparing the manifolds that result from their application to hippocampal place cells, motor cortical neurons during a reaching task, and prefrontal cortical neurons during a multi-behavior task. We find that in many circumstances linear algorithms produce similar results to non-linear methods, although in particular cases where the behavioral complexity is greater, non-linear methods tend to find lower-dimensional manifolds, at the possible expense of interpretability. We demonstrate that these methods are applicable to the study of neurological disorders through simulation of a mouse model of Alzheimer's Disease, and speculate that neural manifold analysis may help us to understand the circuit-level consequences of molecular and cellular neuropathology.

Neuronal signature of spatial decision-making during navigation by freely moving rats by using calcium imaging.

A challenge in spatial memory is understanding how place cell firing contributes to decision-making in navigation. A spatial recency task was created in which freely moving rats first became familiar with a spatial context over several days and thereafter were required to encode and then selectively recall one of three specific locations within it that was chosen to be rewarded that day. Calcium imaging was used to record from more than 1,000 cells in area CA1 of the hippocampus of five rats during the exploration, sample, and choice phases of the daily task. The key finding was that neural activity in the startbox rose steadily in the short period prior to entry to the arena and that this selective population cell firing was predictive of the daily changing goal on correct trials but not on trials in which the animals made errors. Single-cell and population activity measures converged on the idea that prospective coding of neural activity can be involved in navigational decision-making.

Ca2+ imaging of self and other in medial prefrontal cortex during social dominance interactions in a tube test.

The study of social dominance interactions between animals offers a window onto the decision-making involved in establishing dominance hierarchies and an opportunity to examine changes in social behavior observed in certain neurogenetic disorders. Competitive social interactions, such as in the widely used tube test, reflect this decision-making. Previous studies have focused on the different patterns of behavior seen in the dominant and submissive animal, neural correlates of effortful behavior believed to mediate the outcome of such encounters, and interbrain correlations of neural activity. Using a rigorous mutual information criterion, we now report that neural responses recorded with endoscopic calcium imaging in the prelimbic zone of the medial prefrontal cortex show unique correlations to specific dominance-related behaviors. Interanimal analyses revealed cell/behavior correlations that are primarily with an animal's own behavior or with the other animal's behavior, or the coincident behavior of both animals (such as pushing by one and resisting by the other). The comparison of unique and coincident cells helps to disentangle cell firing that reflects an animal's own or the other's specific behavior from situations reflecting conjoint action. These correlates point to a more cognitive rather than a solely behavioral dimension of social interactions that needs to be considered in the design of neurobiological studies of social behavior. These could prove useful in studies of disorders affecting social recognition and social engagement, and the treatment of disorders of social interaction.

Changes in brain activity and connectivity as memories age.

The role of the hippocampus during memory consolidation is not fully understood, with human and animal experiments producing conflicting conclusions. In particular, human lesion studies tend to indicate that the hippocampus gradually becomes independent from memory over years, whilst animal studies suggest that this can happen over days. Tallman et al. (this issue) used fMRI to investigate activity and functional connectivity in the brain at four different time points following memory encoding. Their findings include a decrease in functional connectivity between the hippocampus and parahippocampal cortex with memory age, which supports the system consolidation theory, but also argues against the reduced involvement of the hippocampus over time. This study sheds new light on the neurobiology of memory.

Keggin-type polyoxometalates as Cu(II) chelators in the context of Alzheimer's disease.

Two Keggin polyoxometalates were used as new copper ligands to counteract the effects of CuII(Amyloid-ß) interaction. Their ability to remove CuII from CuII(Amyloid-ß), to stop CuII(Amyloid-ß) induced formation of reactive oxygen species and to restore apo-like self-assembly of CuII(Amyloid-ß) was shown.

Experiential modulation of social dominance in a SYNGAP1 rat model of Autism Spectrum Disorders.

Advances in the understanding of developmental brain disorders such as autism spectrum disorders (ASDs) are being achieved through human neurogenetics such as, for example, identifying de novo mutations in SYNGAP1 as one relatively common cause of ASD. A recently developed rat line lacking the calcium/lipid binding (C2) and GTPase activation protein (GAP) domain may further help uncover the neurobiological basis of deficits in children with ASD. This study focused on social dominance in the tube test using Syngap+/Δ-GAP (rats heterozygous for the C2/GAP domain deletion) as alterations in social behaviour are a key facet of the human phenotype. Male animals of this line living together formed a stable intra-cage hierarchy, but they were submissive when living with wild-type (WT) cage-mates, thereby modelling the social withdrawal seen in ASD. The study includes a detailed analysis of specific behaviours expressed in social interactions by WT and mutant animals, including the observation that when the Syngap+/Δ-GAP mutants that had been living together had separate dominance encounters with WT animals from other cages, the two higher ranking Syngap+/Δ-GAP rats remained dominant whereas the two lower ranking mutants were still submissive. Although only observed in a small subset of animals, these findings support earlier observations with a rat model of Fragile X, indicating that their experience of winning or losing dominance encounters has a lasting influence on subsequent encounters with others. Our results highlight and model that even with single-gene mutations, dominance phenotypes reflect an interaction between genotypic and environmental factors.

iHELMET: A 3D-printing solution for safe endoscopic Ca2+ recording in social neuroscience.

BACKGROUND: In vivo calcium imaging using a microendoscope is a state-of-the-art technique to study the cellular activity inside the brain of freely moving animals such as mice or rats. A problem that can arise in social behaviour tests in rats, or similar size rodents, is that one animal interferes with or may even damage the miniature endoscopic camera attached to the second animal. NEW METHOD: We outline an inexpensive, lightweight, 3D-printed protector (iHELMET) that surrounds but is not in physical contact with the camera, together with details of its design and construction. RESULTS: Using a simple design, we demonstrate successful protection of the endoscope and recording in a social situation such as the social dominance tube test. COMPARISON WITH EXISTING METHODS: The helmet's 3D-printed dimensions can be readily adjusted to work with various micro-endoscopes, which may be more difficult for the only other system of which we are aware. CONCLUSIONS: In addition to camera protection, features of the design aid camera stability, helping to secure more optimal imaging of calcium transients in specific regions of interest during long recording sessions.