Kirrel3 is a cell-adhesion molecule that instructs the formation of specific synapses during brain development in mouse and Kirrel3 variants may be risk factors for autism and intellectual disabilities in humans. Kirrel3 is predicted to undergo alternative splicing but brain isoforms have not been studied. Here, we present the first in-depth characterization of Kirrel3 isoform diversity in brain using targeted, long-read mRNA sequencing of mouse hippocampus. We identified 19 isoforms with predicted transmembrane and secreted forms and show that even rare isoforms generate detectable protein in the brain. We also analyzed publicly-available long-read mRNA databases from human brain tissue and found 11 Kirrel3 isoforms that, similar to mouse, encode transmembrane and secreted forms. In mice and humans, Kirrel3 diversity arises from alternative, independent use of protein-domain coding exons and alternative early translation-stop signals. Intriguingly, the alternatively spliced exons appear at branch points i...

Motivation plays a role when a listener needs to understand speech under acoustically demanding conditions. Previous work has demonstrated pupil-linked arousal being sensitive to both listening demands and motivational state during listening. It is less clear how motivational state affects the temporal evolution of the pupil size and its relation to subsequent behavior. We used an auditory gap detection task ( N  = 33) to study the joint impact of listening demand and motivational state on the pupil size response and examine its temporal evolution. Task difficulty and a listener’s motivational state were orthogonally manipulated through changes in gap duration and monetary reward prospect. We show that participants’ performance decreased with task difficulty, but that reward prospect enhanced performance under hard listening conditions. Pupil size increased with both increased task difficulty and higher reward prospect, and this reward prospect effect was largest under difficult listening conditions. Moreo...

We present a cost-effective, compact foot-print, and open-source Raspberry Pi-based widefield imaging system. The compact nature allows the system to be used for close-proximity dual-brain cortical mesoscale functional-imaging to simultaneously observe activity in two head-fixed animals in a staged social touch-like interaction. We provide all schematics, code, and protocols for a rail system where head-fixed mice are brought together to a distance where the macrovibrissae of each mouse make contact. Cortical neuronal functional signals (GCaMP6s; genetically encoded Ca2+ sensor) were recorded from both mice simultaneously before, during, and after the social contact period. When the mice were together, we observed bouts of mutual whisking and cross-mouse correlated cortical activity across the cortex. Correlations were not observed in trial-shuffled mouse pairs, suggesting that correlated activity was specific to individual interactions. Whisking-related cortical signals were observed during the period whe...

Alcohol use disorder (AUD) is a complex psychiatric disease characterized by periods of heavy drinking and periods of withdrawal. Chronic exposure to ethanol causes profound neuroadaptations in the extended amygdala, which cause allostatic changes promoting excessive drinking. The bed nucleus of the stria terminalis (BNST), a brain region involved in both excessive drinking and anxiety-like behavior, shows particularly high levels of pituitary adenylate cyclase-activating polypeptide (PACAP), a key mediator of the stress response. Recently, a role for PACAP in withdrawal-induced alcohol drinking and anxiety-like behavior in alcohol-dependent rats has been proposed; whether the PACAP system of the BNST is also recruited in other models of alcohol addiction and whether it is of local or nonlocal origin is currently unknown. Here, we show that PACAP immunoreactivity is increased selectively in the BNST of C57BL/6J mice exposed to a chronic, intermittent access to ethanol. While pituitary adenylate cyclase-act...

In the article “Dopamine Receptor Type 2-Expressing Medium Spiny Neurons in the Ventral Lateral Striatum Have a Non-REM Sleep-Induce Function,” by Tomonobu Kato, Kenji F. Tanaka, and …

Dysfunction in the gene SCN2A , which encodes the voltage-gated sodium channel Nav1.2, is strongly associated with neurodevelopmental disorders including autism spectrum disorder and intellectual disability (ASD/ID). This dysfunction typically manifests in these disorders as a haploinsufficiency, where loss of one copy of a gene cannot be compensated for by the other allele. Scn2a haploinsufficiency affects a range of cells and circuits across the brain, including associative neocortical circuits that are important for cognitive flexibility and decision-making behaviors. Here, we tested whether Scn2a haploinsufficiency has any effect on a dynamic foraging task that engages such circuits. Scn2a +/− mice and wild-type (WT) littermates were trained on a choice behavior where the probability of reward between two options varied dynamically across trials and where the location of the high reward underwent uncued reversals. Despite impairments in Scn2a -related neuronal excitability, we found that both male and ...

Spatial memories are represented by hippocampal place cells during navigation. This spatial code is dynamic, undergoing changes across time, known as representational drift, and across changes in internal state, even while navigating the same spatial environment with consistent behavior. A dynamic code may provide the hippocampus a means to track distinct epochs of experience that occur at different times or during different internal states and update spatial memories. Changes to the spatial code include place fields (PFs) that remap to new locations and place fields that vanish, while others are stable. However, what determines place field fate across epochs remains unclear. We measured the lap-by-lap properties of place cells in mice during navigation for a block of trials in a rewarded virtual environment. We then determined the position of the place fields in another block of trials in the same spatial environment either separated by a day (a distinct temporal epoch) or during the same session but with...

Accurately and quantitatively describing mouse behavior is an important area. Although advances in machine learning have made it possible to track their behaviors accurately, reliable classification of behavioral sequences or syllables remains a challenge. In this study, we present a novel machine learning approach, called SaLSa (a combination of semi-automatic labeling and long short-term memory-based classification), to classify behavioral syllables of mice exploring an open field. This approach consists of two major steps. First, after tracking multiple body parts, spatial and temporal features of their egocentric coordinates are extracted. A fully automated unsupervised process identifies candidates for behavioral syllables, followed by manual labeling of behavioral syllables using a graphical user interface (GUI). Second, a long short-term memory (LSTM) classifier is trained with the labeled data. We found that the classification performance was marked over 97%. It provides a performance equivalent to...

The ventromedial motor thalamus (VM) is implicated in multiple motor functions and occupies a central position in the cortico-basal ganglia-thalamocortical loop. It integrates glutamatergic inputs from motor cortex (MC) and motor-related subcortical areas, and it is a major recipient of inhibition from basal ganglia. Previous in vitro experiments performed in mice showed that dopamine depletion enhances the excitability of thalamocortical (TC) neurons in VM due to reduced M-type potassium currents. To understand how these excitability changes impact synaptic integration in vivo , we constructed biophysically detailed mouse VM TC model neurons fit to normal and dopamine-depleted conditions, using the NEURON simulator. These models allowed us to assess the influence of excitability changes with dopamine depletion on the integration of synaptic inputs expected in vivo . We found that VM neuron models in the dopamine-depleted state showed increased firing rates with the same synaptic inputs. Synchronous bursti...

Large interindividual variability in the effects of low-intensity transcranial electrical stimulation (tES) considerably limits its potential for clinical applications. It has been recently proposed that individualizing stimulation dose by accounting for interindividual anatomic differences would reduce the variability in electric fields (E-fields) over the targeted cortical site and therefore produce more consistent behavioral outcomes. However, improvement in behavioral outcomes following individualized dose tES has never been compared with that of conventional fixed dose tES. In this study, we aimed to empirically evaluate the effect of individualized dose tES on behavior and further compare it with the effects of sham and fixed dose stimulations. We conducted a single-blinded, sham-controlled, repeated-measures study to examine the impact of transcranial direct current stimulation on motor learning and that of transcranial alternating current stimulation on the working memory of 42 healthy adult indivi...