Fragile X syndrome is a leading cause of intellectual disability and autism spectrum disorder, for which therapies are limited. A mouse model of Fragile X syndrome, the Fmr1 knockout (KO) mouse, has been particularly valuable for interrogating the molecular, cellular, and circuit mechanisms that underlie the neurological deficits seen in this syndrome. Key deficits in Fragile X syndrome include impairments in social behaviors, cognition, and motor learning. Given the difficulties in extrapolating complex human behaviors to mouse models, motor behaviors are a particularly tractable form of learning to study in the mouse. We investigated a form of forelimb reach learning in both male and female Fmr1 KO mice, quantifying different parameters of the task using both manual analysis and DeepLabCut-based tracking of reach trajectories. While Fmr1 KO mice show impaired learning overall, our results showed that the presence or absence of a cue that signals reward alleviated some of the deficits. In addition to a si...

Proteomic studies have generated robust assessments of protein abundance changes in Alzheimer’s disease (AD); however, identifying how the protein abundance changes affect specific biological processes remains a challenge. To address these hurdles, we used a multi-network computational analysis approach that integrated dendritic spine morphometry data with mass spectrometry-based proteomics from the same individuals. The samples exhibited a range of AD neuropathology and were categorized into three groups: controls, asymptomatic AD, and AD cases. Multiplex tandem mass tag mass spectrometry proteomic data (N = 8,212 proteins) was generated on Brodmann area 46 (BA46) dorsolateral prefrontal cortex (DLPFC) human samples (N = 41, 23 males and 18 females), from which dendritic spine morphometry analysis existed. To integrate the multi-scale data types, two computational network analysis methods were performed, including WeiGhted co-expression network analysis (WGCNA) and SpeakEasy2 (SE2). Both WGCNA and SE2 rev...

Elucidating the neural substrates of Pavlovian reward learning requires reliable behavioral readouts. In conditioned magazine approach studies, rodents express reward expectancy by approaching the food magazine during cues that predict reward. This behavior is typically quantified using one of three measures: number of head entries, percentage of time in the magazine, or latency to respond. Yet these measures often diverge within the same discrimination task, making reliance on a single metric problematic. At the individual level, some animals express discrimination learning most clearly in one measure while showing little or no learning in the others, and animals may even switch their preferred measure across training. Reporting only one measure therefore risks underestimating the ability of a subset of animals. At the group level, sampling error can produce apparent differences across replications of the same design, limiting replicability. Moreover, brain manipulations can alter response topography, suc...

The amount of time previously spent awake or asleep strongly impacts the sleep electroencephalogram (EEG), especially slow waves during nonrapid-eye-movement (NREM) sleep. These effects on the sleep EEG meaningfully interact with age and to a lesser extent developmental disorders such as attention-deficit hyperactivity disorder (ADHD). We aimed to determine whether EEG oscillations during wakefulness were likewise affected by the interaction of sleep and development, using data collected from 163 participants aged 3–25 years old (62 female). We analyzed age- and sleep-dependent changes in two measures of oscillatory activity (amplitudes and density) and aperiodic activity (offsets and exponents). Finally, we compared wake EEG in children with ADHD ( N  = 58) to neurotypical controls, with habitual good sleep quality required for inclusion. We found that oscillation amplitudes exhibited the same dynamics as sleep slow waves: decreasing with age, decreasing after sleep, and the overnight decrease decreasing ...

Protein tyrosine phosphatase receptor type Z1 ( Ptprz1 ) is one of the most abundantly expressed and enriched genes in astrocytes during development, yet its function in astrocytes is unknown. Using an astrocyte–neuron coculture system, we found that knockdown of Ptprz1 in astrocytes significantly impaired astrocyte branching morphogenesis. To investigate the function of Ptprz1 in astrocytes during brain development, we generated a Ptprz1 conditional knock-out mouse and deleted Ptprz1 from astrocytes postnatally, after the bulk of astrogenesis is complete. At postnatal day 21, we found subtle changes in astrocyte morphology and a reduction in the density of colocalized pre- and postsynaptic excitatory synapse markers across multiple layers of the visual cortex in both male and female mice, suggesting important functions for astrocytic Ptprz1 in both astrocyte morphogenesis and synaptogenesis. Ptprz1 is expressed in several neural cell types, including radial glial stem cells and oligodendrocyte progenitor ...

Cortical neurons in sensory areas undergo a protracted process of postnatal maturation that includes changes in membrane properties, synaptic drive, and connectivity. The completion of this process is associated with the closure of critical periods for experience-dependent plasticity in visual, auditory, and somatosensory cortices. Whether these findings extend to the postnatal development of cortical circuits for taste is currently unknown. Taste receptor cells in the taste buds reliably fire action potentials in response to taste stimuli by the third postnatal week and show extended refinement of membrane excitability into adulthood. Taste responsive neurons in the nucleus of the solitary tract show reorganization of peripheral nerve terminals (NTS) over a timeline comparable to taste buds. However, no study to date investigated the postnatal development of neurons in the gustatory cortex (GC). Here, we focused on pyramidal neurons in the deep layers of GC in acute slices from male and female mice and co...

Accurate characterization of auditory pathway responses is critical for understanding neural disorders that affect hearing, including both peripheral and central deficits, as well as broader neurodevelopmental conditions. Animal models provide a way to investigate auditory circuit activation with high spatial and temporal resolution. Here, we first assessed behavioral detection of pure tones (PT) and narrowband noise (NBN) stimuli in male rats, revealing that NBN targets were detected at lower amplitudes than PT targets, consistent with human auditory detection patterns. We then compared these behavioral results with neural responses recorded in female rats’ medial geniculate body (MGB), a thalamic relay to the auditory cortex. Using high-density multichannel recordings, we found that NBN stimuli elicited greater neural sensitivity at low amplitudes, whereas PT stimuli evoked faster responses and higher peak firing rates. MGB units achieved maximal frequency discrimination at amplitudes close to detection ...

Elucidating the neural substrates of pavlovian reward learning requires reliable behavioral readouts. In conditioned magazine approach studies, rodents express reward expectancy by approaching the food magazine during cues that predict reward. This behavior is typically quantified using one of three measures: number of head entries, percentage of time in the magazine, or latency to respond. Yet these measures often diverge within the same discrimination task, making reliance on a single metric problematic. At the individual level, some animals express discrimination learning most clearly in one measure while showing little or no learning in the others, and animals may even switch their preferred measure across training. Reporting only one measure therefore risks underestimating the ability of a subset of animals. At the group level, sampling error can produce apparent differences across replications of the same design, limiting replicability. Moreover, brain manipulations can alter response topography, suc...

Extinction-reinstatement paradigms have been used to study reward-seeking for both food and drug rewards. The nucleus accumbens (NAc) is of particular interest in reinstatement due to its ability to energize motivated behavior. Previous work found that suppression of neuronal activity or dopamine signaling in NAc reduces reinstatement of food-seeking. Here we used fiber photometry and sensor multiplexing (red-shifted dopamine sensor and genetically-encoded calcium indicator) to measure dopamine and calcium in NAc core of male and female rats on each day of an extinction-reinstatement paradigm with food reward to determine how signals vary across task phases. During self-administration training, we detected positive dopamine transients that initially followed lever pressing but moved earlier in time as training progressed. A post-press dopamine decrease also emerged with training. For calcium, a decrease from baseline occurred after the press and became more prominent across training. Both patterns were red...

The flexible control of working memory (WM) requires prioritizing immediately task-relevant information while maintaining information with potential future relevance in a deprioritized state. Using double-serial retrocuing (DSR) with simultaneous EEG recording, we investigated how single pulses of transcranial magnetic stimulation (spTMS) to right intraparietal sulcus impacts neural representations of unprioritized memory items (UMI), relative to irrelevant memory items (IMI) that are no longer needed for the trial. Twelve human participants (8 female) performed DSR plus a single-retrocue task, while spTMS was delivered during delay periods. Multivariate pattern analysis revealed that spTMS restored decodability of the UMI concurrent with stimulation and that of the IMI several timesteps later, after the evoked effects of spTMS were no longer present in the EEG signal. This effect was carried by the alpha (8–13 Hz) and low-beta (13–20 Hz) frequency bands. Analyses of the raw EEG signal showed two effects s...