Environmental enrichment (EE) is beneficial for brain development and function, but our understanding of its capacity to drive circuit repair, the underlying mechanisms, and how this might vary with age remains limited. Ten-m3 knock-out (KO) mice exhibit a dramatic and stereotyped mistargeting of ipsilateral retinal inputs to the thalamus, resulting in visual deficits. We have recently shown a previously unexpected capacity for EE during early postnatal life (from birth for six weeks) to drive the partial elimination of miswired axonal projections, along with a recovery of visually mediated behavior, but the timeline of this repair was unclear. Here, we reveal that with just 3.5 weeks of EE from birth, Ten-m3 KOs exhibit a partial behavioral rescue, accompanied by pruning of the most profoundly miswired retinogeniculate terminals. Analysis suggests that the pruning is underway at this time point, providing an ideal opportunity to probe potential mechanisms. With the shorter EE-period, we found a localized ...

Accurate and efficient quantification of animal behavior facilitates the understanding of the brain. An emerging approach within machine learning (ML) field is to combine multiple ML-based algorithms to quantify animal behavior. These so-called hybrid models have emerged because of limitations associated with supervised [e.g., random forest (RF)] and unsupervised [e.g., hidden Markov model (HMM)] ML models. For example, RF models lack temporal information across video frames, and HMM latent states are often difficult to interpret. We sought to develop a hybrid model, and did so in the context of a study of mouse risk assessment behavior. We used DeepLabCut to estimate the positions of mouse body parts. Positional features were calculated using DeepLabCut outputs and were used to train RF and HMM models with equal number of states, separately. The per-frame predictions from RF and HMM models were then passed to a second HMM model layer (“reHMM”). The outputs of the reHMM layer showed improved interpretabili...

The noradrenergic locus coeruleus (LC) is among the earliest sites of tau and α-synuclein pathology in Alzheimer’s disease (AD) and Parkinson’s disease (PD), respectively. The onset of these pathologies coincides with loss of noradrenergic fibers in LC target regions and the emergence of prodromal symptoms including sleep disturbances and anxiety. Paradoxically, these prodromal symptoms are indicative of a noradrenergic hyperactivity phenotype, rather than the predicted loss of norepinephrine (NE) transmission following LC damage, suggesting the engagement of complex compensatory mechanisms. Because current therapeutic efforts are targeting early disease, interest in the LC has grown, and it is critical to identify the links between pathology and dysfunction. We employed the LC-specific neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4), which preferentially damages LC axons, to model early changes in the LC-NE system pertinent to AD and PD in male and female mice. DSP-4 (two doses of 50 mg/kg...

Sleep facilitates memory storage and even brief periods of sleep loss lead to impairments in memory, particularly memories that are hippocampus dependent. In previous studies, we have shown that the deficit in memory seen after sleep loss is accompanied by deficits in synaptic plasticity. Our previous work has also found that sleep deprivation (SD) is associated with reduced levels of cyclic adenosine monophosphate (cAMP) in the hippocampus and that the reduction of cAMP mediates the diminished memory observed in sleep-deprived animals. Based on these findings, we hypothesized that cAMP acts as a mediator for not only the cognitive deficits caused by sleep deprivation, but also the observed deficits in synaptic plasticity. In this study, we expressed the heterologous Drosophila melanogaster Gαs-protein-coupled octopamine receptor (DmOctβ1R) in mouse hippocampal neurons. This receptor is selectively activated by the systemically injected ligand (octopamine), thus allowing us to increase cAMP levels in hippo...

Injuries to peripheral nerves are frequent, yet no drug therapies are available for effective nerve repair. The slow growth rate of axons and inadequate access to growth factors challenge natural repair of nerves. A better understanding of the molecules that can promote the rate of axon growth may reveal therapeutic opportunities. Molecular profiling of injured neurons at early intervals of injury, when regeneration is at the maximum, has been the gold standard for exploring growth promoters. A complementary in vitro regenerative priming model was recently shown to induce enhanced outgrowth in adult sensory neurons. In this work, we exploited the in vitro priming model to reveal novel candidates for adult nerve regeneration. We performed a whole-tissue proteomics analysis of the in vitro primed dorsal root ganglia (DRGs) from adult SD rats and compared their molecular profile with that of the in vivo primed, and control DRGs. The proteomics data generated are available via ProteomeXchange with identifier P...

Electrophysiological studies with behaving nonhuman primates often require the separation of animals from their social group as well as partial movement restraint to perform well-controlled experiments. When the research goal per se does not mandate constraining the animals’ movements, there are often still experimental needs imposed by tethered data acquisition. Recent technological advances meanwhile allow wireless neurophysiological recordings at high band-width in limited-size enclosures. Here, we demonstrate wireless neural recordings at single unit resolution from unrestrained rhesus macaques while they performed self-paced, structured visuomotor tasks on our custom-built, stand-alone touchscreen system [eXperimental Behavioral Instrument (XBI)] in their home environment. We were able to successfully characterize neural tuning to task parameters, such as visuo-spatial selectivity during movement planning and execution, as expected from existing findings obtained via setup-based neurophysiology record...

Down syndrome cell adhesion molecule ( DSCAM ) is located on human chromosome 21 and triplicated in Down syndrome. DSCAM encodes an Ig superfamily cell surface receptor found in both vertebrates and invertebrates. Alternative splicing is more widespread in mammals compared with invertebrates, but Drosophila Dscam1 is remarkably more complex in this respect than its human counterpart. However, both vertebrate and invertebrate DSCAM/Dscam share a similar critical function—neural wiring (Schmucker and Chen, 2009). To create both the accuracy and complexity of neural wiring, one of the indispensable characteristics of neurons is the ability to express a wide repertoire of cell surface receptors. This ensures both specificity and selectivity. Drosophila Dscam1 is one such extraordinary example. Dscam1 undergoes alternative splicing to generate ∼38,000 receptor isoforms. Dscam1 protein has an intracellular C terminus, a transmembrane domain, and an ectodomain with 10 Ig domains and 6 fibronectin type III repeat...

A central question in neuroscience is how sensory inputs are transformed into percepts. At this point, it is clear that this process is strongly influenced by prior knowledge of the sensory environment. Bayesian ideal observer models provide a useful link between data and theory that can help researchers evaluate how prior knowledge is represented and integrated with incoming sensory information. However, the statistical prior employed by a Bayesian observer cannot be measured directly, and must instead be inferred from behavioral measurements. Here, we review the general problem of inferring priors from psychophysical data, and the simple solution that follows from assuming a prior that is a Gaussian probability distribution. As our understanding of sensory processing advances, however, there is an increasing need for methods to flexibly recover the shape of Bayesian priors that are not well approximated by elementary functions. To address this issue, we describe a novel approach that applies to arbitrary...

The study used machine learning to predict The American Spinal Injury Association Impairment Scale (AIS) scores for newly injured spinal cord injury patients at hospital discharge time from hospital admission data. Additionally, machine learning was used to analyze the best model for feature importance to validate the criticality of the AIS score and highlight relevant demographic details. The data used for training machine learning models was from the National Spinal Cord Injury Statistical Center (NSCISC) database of U.S. spinal cord injury patient details. Eighteen real features were used from 417 provided features, which mapped to 53 machine learning features after processing. Eight models were tuned on the dataset to predict AIS scores, and Shapely analysis was performed to extract the most important of the 53 features. Patients within the NSCISC database who sustained injuries were between 1972 and 2016 after data cleaning ( n  = 20,790). Outcomes were test set multiclass accuracy and aggregated Shap...

Wnt signaling is crucial for synapse and cognitive function. Indeed, deficient Wnt signaling is causally related to increased expression of DKK1, an endogenous negative Wnt regulator, and synapse loss, both of which likely contribute to cognitive decline in Alzheimer’s disease (AD). Increasingly, AD research efforts have probed the neuroinflammatory role of microglia, the resident immune cells of the CNS, which have furthermore been shown to be modulated by Wnt signaling. The DKK1 homolog DKK2 has been previously identified as an activated response and/or disease-associated microglia (DAM/ARM) gene in a mouse model of AD. Here, we performed a detailed analysis of DKK2 in mouse models of neurodegeneration, and in human AD brain. In APP/PS1 and APPNL-G-F AD mouse model brains as well as in SOD1G93A ALS mouse model spinal cords, but not in control littermates, we demonstrated significant microgliosis and microglial Dkk2 mRNA upregulation in a disease-stage-dependent manner. In the AD models, these DAM/ARM Dkk...