Biology subjects

Bradley, S. P.

Publications and source records attributed to Bradley, S. P..

4 recordsLinked to original sources

bioRxiv2026

Preserved social development but impaired executive function in a Shank3-deficient rat model of Phelan-McDermid syndrome

Phelan-McDermid syndrome (PMS) is a genetic neurodevelopmental disorder caused by a microdeletion within chromosome 22q13.3 1-6, and accounts for [~]1-3% of cases of autism spectrum disorders (ASD). Individuals with PMS typically present with neonatal hypotonia, severe speech delay, intellectual disability, motor impairments, and autism-related features, although additional manifestations such as epilepsy, sleep disturbances, and developmental regression are common. As in ASD, there is considerable heterogeneity in cognitive and behavioral impairments in PMS, making it difficult to determine which features arise directly from SHANK3/Shank3 deficiency and how deficits manifest across development. In the present study, we transferred the targeted Shank3 mutation, previously characterized on the Sprague Dawley background, onto the Long-Evans strain and performed a longitudinal behavioral assessment of Shank3-deficient rats from infancy to adulthood. The rats were evaluated for delays in early sensory and motor development, and ultrasonic vocalizations as neonates, social behavior, short term memory and gait as juveniles, and cognitive-executive dysfunction using a touchscreen-based visual discrimination and reversal learning task as adults. Despite profound reductions and/or complete loss of Shank3 protein expression, heterozygous and homozygous male and female rats showed normal physical and neurological reflexes across development, yet female Shank3 knockout pups showed a selective reduction in distress-associated ultrasonic vocalizations. As juveniles, subtle abnormalities emerged in short-term memory and limb coordination, while social preference for novelty and recognition was normal. Prominent behavioral abnormalities were observed in adults characterized by rapid and error-prone responding to visual stimuli during discrimination learning and reversal. These data suggest that rats with complete or partial Shank3 deficiency produce a selective behavioral profile in which high-order cognitive dysfunction is more pronounced than deficits in basic sensorimotor or select social behaviors. More broadly, these findings highlight executive dysfunction as a key consequence of the loss of Shank3. For the first time, we report the loss of Shank3 expression on a Long-Evans background strain as a valuable translational tool for investigating cognitive dysfunction and therapeutic windows in Shank3-associated disorders.

animal behavior and cognition↗

bioRxiv2024

Galanin receptor 1 expressing neurons in hippocampal-prefrontal circuitry modulate goal directed attention and impulse control

Neuropeptides like galanin are increasingly recognized as modulators of cognitive pathways. Galanin has been implicated in a wide range of pathological conditions in which frontal and temporal structures are compromised. Recently, we discovered that direct pharmacological stimulation of galanin receptor type 1 (GalR1) in the ventral prefrontal cortex (vPFC) and ventral hippocampus (vHC) caused opposing effects on attention and impulse control behaviors. In the present study, we investigate how neurons expressing GalR1 in these two areas differentially contribute to these behaviors. First, using multiplex fluorescent in situ-hybridization, we established that GalR1 is predominantly expressed in glutamatergic neurons in both the vPFC and vHC. Rats were assessed in their visuospatial attention and impulse control behaviors using the 5- Choice task. We developed a novel viral approach to gain genetic access to GalR1-expressing neurons in the vPFC and vHC, and found that optogenetic excitation of GalR1 expressing neurons in the vPFC, but not vHC, selectively disrupted attention. Finally, using fiber photometry, we measured the bulk calcium dynamics in GalR1-expressing neurons and discovered that GalR1- expressing neurons in the vPFC and vHC showed opposing activity; increased activity in neurons in the vPFC corresponded to correct, attentive actions, whereas activity in the vHC signaled impulsive errors. This region- and response-specific intrinsic activity of galanin, mediated by subclasses of neurons in frontotemporal circuitry participates in shaping the expression of executive-control behaviors that often go awry in various disorders of mental health.

neuroscience↗

bioRxiv2024

Improving reproductive success in captive marmosets through active female choice

The recent upsurge in the use of common marmosets (Callithrix jacchus) as a desirable model for high priority biomedical research has challenged local and global suppliers struggling to provide sufficient numbers of marmosets for large scale projects. Scientific research laboratories are increasingly establishing institutional breeding colonies, in part to combat the resulting shortage and high cost of commercially available animals, and in part to have maximum control over research lines involving reproduction and development. For such laboratories, efficient marmoset breeding can be challenging and time consuming. Random male/female pairings are often unsuccessful, with intervals of several months before attempting alternate pairings. Here we address this challenge through a behavioral task that promotes self-directed female selection of potential mates to increase the efficiency of breeding in captive marmosets. We created a partner preference test ( love maze) in which nulliparous females (n=12) had the opportunity to select between two eligible males (n=23) at a time, in a forced choice test. In this test, both males usually displayed sexual solicitations. However, the female would clearly indicate her preference for one. Most commonly, the female actively ignored the non-preferred male and directed overt prosocial behaviors (e.g. proceptive tongue-flicking, approach and grooming) to the preferred male. Moreover, once a male was selected in this context, the female would continue to prefer him over other males in three consecutive testing sessions. Compared with random pairings, this directed female choice showed a 2.5-fold improvement in breeding within 90 days compared to random pairings. This cost-effective and straightforward pairing practice can be used to enhance breeding efficiency in both small and large marmoset colonies.

animal behavior and cognition↗

bioRxiv2024

Cingulate cortex shapes early postnatal development of social vocalizations

The social dynamics of vocal behavior has major implications for social development in humans. We asked whether early life damage to the anterior cingulate cortex (ACC), which is closely associated with socioemotional regulation more broadly, impacts the normal development of vocal expression. The common marmoset provides a unique opportunity to study the developmental trajectory of vocal behavior, and to track the consequences of early brain damage on aspects of social vocalizations. We created ACC lesions in neonatal marmosets and compared their pattern of vocalization to that of age-matched controls throughout the first 6 weeks of life. We found that while early life ACC lesions had little influence on the production of vocal calls, developmental changes to the quality of social contact calls and their associated sequential and acoustic characteristics were compromised. These animals made fewer social contact calls, and when they did, they were short, loud and monotonic. We further determined that damage to ACC in infancy results in a permanent alteration in downstream brain areas known to be involved in social vocalizations, such as the amygdala and periaqueductal gray. Namely, in the adult, these structures exhibited diminished GABA-immunoreactivity relative to control animals, likely reflecting disruption of the normal inhibitory balance following ACC deafferentation. Together, these data indicate that the normal development of social vocal behavior depends on the ACC and its interaction with other areas in the vocal network during early life.

neuroscience↗