Learning the spatial layout of a novel environment is associated with dynamic activity changes in the hippocampus and in medial parietal areas. With advancing age, the ability to learn spatial environments deteriorates substantially but the underlying neural mechanisms are not well understood. Here, we report findings from a behavioral and a fMRI experiment where healthy human older and younger adults of either sex performed a spatial learning task in a photorealistic virtual environment. We modeled individual learning states using a Bayesian state-space model and found that activity in retrosplenial cortex/parieto-occipital sulcus and anterior hippocampus did not change systematically as a function learning in older compared to younger adults across repeated episodes in the environment. Moreover, effective connectivity analyses revealed that the age-related learning deficits were linked to an increase in hippocampal excitability. Together, these results provide novel insights into how human aging affects ...

The neural mechanisms that allow animals to adapt their previously learned associations in response to changes in the environment remain poorly understood. To probe the synaptic mechanisms that mediate such adaptive behavior, we trained mice on an auditory-motor reversal task, and tracked changes in the strength of corticostriatal synapses associated with the formation of learned associations. Using a ChR2-based electrophysiological assay in acute striatal slices, we measured the strength of these synapses after animals learned to pair auditory stimuli with specific actions. Here, we report that the pattern of synaptic strength initially established by learning remains unchanged even when the task contingencies are reversed. Our findings reveal that synaptic changes associated with the initial acquisition of this task are not erased or overwritten, and that behavioral reversal of learned associations may recruit a separate neural circuit. These results suggest a more complex role of the striatum in regulat...

Computer vision approaches have made significant inroads into offline tracking of behavior and estimating animal poses. In particular, because of their versatility, deep-learning approaches have been gaining attention in behavioral tracking without any markers. Here, we developed an approach using DeepLabCut for real-time estimation of movement. We trained a deep-neural network (DNN) offline with high-speed video data of a mouse whisking, then transferred the trained network to work with the same mouse, whisking in real-time. With this approach, we tracked the tips of three whiskers in an arc and converted positions into a TTL output within behavioral time scales, i.e., 10.5 ms. With this approach, it is possible to trigger output based on movement of individual whiskers, or on the distance between adjacent whiskers. Flexible closed-loop systems like the one we have deployed here can complement optogenetic approaches and can be used to directly manipulate the relationship between movement and neural activity.

Voluntary movements are usually preceded by a slow, negative-going brain signal over motor areas, the so-called readiness potential (RP). To date, the exact nature and causal role of the RP in movement preparation have remained heavily debated. Although the RP is influenced by several motorical and cognitive factors, it has remained unclear whether people can learn to exert mental control over their RP, for example, by deliberately suppressing it. If people were able to initiate spontaneous movements without eliciting an RP, this would challenge the idea that the RP is a necessary stage of the causal chain leading up to a voluntary movement. We tested the ability of participants to control the magnitude of their RP in a neurofeedback experiment. Participants performed self-initiated movements, and after every movement, they were provided with immediate feedback about the magnitude of their RP. They were asked to find a strategy to perform voluntary movements such that the RPs were as small as possible. We ...

Mutations in the presenilin genes ( PS1 , PS2 ) have been linked to the majority of familial Alzheimer’s disease (AD). Although great efforts have been made to investigate pathogenic PS mutations, which ultimately cause an increase in the toxic form of β-amyloid (Aβ), the intrinsic physiological functions of PS in human neurons remain to be determined. In this study, to investigate the physiological roles of PS in human neurons, we generated PS1 conditional knock-out (KO) induced pluripotent stem cells (iPSCs), in which PS1 can be selectively abrogated under Cre transduction with or without additional PS2 KO. We showed that iPSC-derived neural progenitor cells (NPCs) do not confer a maintenance ability in the absence of both PS1 and PS2, showing the essential role of PS in Notch signaling. We then generated PS -null human cortical neurons, where PS1 was intact until full neuronal differentiation occurred. Aβ40 production was reduced exclusively in human PS1 / PS2 -null neurons along with a concomitant accu...

We can focus visuospatial attention by covertly attending to relevant locations, moving our eyes, or both simultaneously. How does shifting versus holding covert attention during fixation compare with maintaining covert attention across saccades? We acquired human fMRI data during a combined saccade and covert attention task. On Eyes-fixed trials, participants either held attention at the same initial location (“hold attention”) or shifted attention to another location midway through the trial (“shift attention”). On Eyes-move trials, participants made a saccade midway through the trial, while maintaining attention in one of two reference frames: the “retinotopic attention” condition involved holding attention at a fixation-relative location but shifting to a different screen-centered location, whereas the “spatiotopic attention” condition involved holding attention on the same screen-centered location but shifting relative to fixation. We localized the brain network sensitive to attention shifts (shift > ...

Motor adaptation is commonly thought to be a trial-and-error process in which the accuracy of movement improves with repetition of behavior. We challenged this view by testing whether erroneous movements are necessary for motor adaptation. In the eye movement system, the association between movements and errors can be disentangled, since errors in the predicted stimulus trajectory can be perceived even without movements. We modified a smooth pursuit eye movement adaptation paradigm in which monkeys learn to make an eye movement that predicts an upcoming change in target direction. We trained the monkeys to fixate on a target while covertly, an additional target initially moved in one direction and then changed direction after 250 ms. The monkeys showed a learned response to infrequent probe trials in which they were instructed to follow the moving target. Additional experiments confirmed that probing learning or residual eye movements during fixation did not drive learning. These results show that motor ad...

Angelman syndrome (AS) is a neurodevelopmental disorder with unique behavioral phenotypes, seizures, and distinctive electroencephalographic (EEG) patterns. Recent studies identified motor, social communication, and learning and memory deficits in a CRISPR engineered rat model with a complete maternal deletion of the Ube3a gene. It is unknown whether this model recapitulates other aspects of the clinical disorder. We report here the effect of Ube3a maternal deletion in the rat on epileptiform activity, seizure threshold, and quantitative EEG. Using video-synchronized EEG (vEEG) monitoring, we assessed spectral power and epileptiform activity early postnatally through adulthood. While EEG power was similar to wild-type (WT) at 1.5 weeks postnatally, at all other ages analyzed, our findings were similar to the AS phenotype in mice and humans with significantly increased δ power. Analysis of epileptiform activity in juvenile and adult rats showed increased time spent in epileptiform activity in AS compared wi...

For some individuals, social stress is a risk factor for psychiatric disorders characterized by adolescent onset, prefrontal cortex (PFC) dysfunction and cognitive impairments. Social stress may be particularly harmful during adolescence when dopamine (DA) axons are still growing to the PFC, rendering them sensitive to environmental influences. The guidance cue Netrin-1 and its receptor, DCC, coordinate to control mesocorticolimbic DA axon targeting and growth during this age. Here, we adapted the accelerated social defeat (AcSD) paradigm to expose male mice to social stress in either adolescence or adulthood and categorized them as “resilient” or “susceptible” based on social avoidance behavior. We examined whether stress would alter the expression of DCC and Netrin-1 in mesolimbic DA regions and would have enduring consequences on PFC DA connectivity and cognition. While in adolescence the majority of mice are resilient but exhibit risk-taking behavior, AcSD in adulthood leads to a majority of susceptibl...

The lateral orbitofrontal cortex (LOFC) is thought to encode information associated with consumption of rewarding substances and is essential for flexible decision-making. Indeed, firing patterns of LOFC neurons are modulated following changes in reward value associated with an action outcome relationship. Damage to the LOFC impairs behavioral flexibility in humans and is associated with suboptimal performance in reward devaluation protocols in rodents. As chronic intermittent ethanol (CIE) exposure also impairs OFC-dependent behaviors, we hypothesized that CIE exposure would alter LOFC neuronal activity during alcohol drinking, especially under conditions when the reward value of ethanol was modulated by aversive or appetitive tastants. To test this hypothesis, we monitored LOFC activity using GCaMP6f fiber photometry in mice receiving acute injections of ethanol and in those trained in operant ethanol self-administration. In naive mice, an acute injection of ethanol caused a dose-dependent decrease in th...