Biology subjects

Halladay, L. R.

Publications and source records attributed to Halladay, L. R..

4 recordsLinked to original sources

bioRxiv2025

Genetic diversity shapes behavioral outcomes and reveals sex differences in mice exposed to early life stress

Understanding how genetic variability shapes responses to environmental and developmental factors is critical for advancing translational neuroscience. However, most preclinical studies rely on inbred mouse strains that do not capture the genetic complexity of human populations. One key area of translational research focuses on identifying the neural and behavioral consequences of early life trauma. Rodent models of childhood neglect, such as maternal separation with early weaning (MSEW), have been used in isogenic mouse strains like C57BL/6J (B6) to identify behavioral domains and neural loci of deficits stemming from exposure to MSEW. To understand how genetic diversity may contribute to the outcomes produced by MSEW, and thus inform future studies on the topic, we utilized the Jackson Laboratory Diversity Outbred (DO) line, a population derived from eight founder strains that exhibit broad genetic and phenotypic heterogeneity. We first compared MSEW effects on social behavior in DO mice versus B6 mice, because we have previously found social behavior deficits in B6 mice with a history of MSEW. Indeed, we established that MSEW incited social motivation deficits in DO mice, in a sex-specific manner. We then expanded our investigation of DO mice to test MSEW-related changes in anxiety-like behavior, fear learning and expression, and reward-seeking. Results revealed that MSEW produces distinct, sex-specific phenotypes: female DO mice displayed reduced social motivation and elevated anxiety-like behavior, while male DO mice showed attenuated CS-evoked fear expression and diminished reward-seeking behavior. Additionally, immunohistochemical analysis revealed increased Fos expression in the paraventricular nucleus of the hypothalamus (PVN) in MSEW-exposed DO mice, both at baseline and following acute stress. These findings highlight the importance of incorporating genetically diverse models to better capture the nuances of early life adversity-related outcomes relevant to human populations.

neuroscience↗

bioRxiv2023

Nature and nurture: comparing mouse behavior in classic versus revised anxiety-like and social behavioral assays in genetically or environmentally defined groups

Widely used rodent anxiety assays like the elevated plus maze (EPM) and the open field test (OFT) are often conflated with rodents natural preference for dark over light environments or protected over open spaces. The EPM and OFT have been used for many decades, yet have also been criticized by generations of behavioral scientists. Several years ago, two revised anxiety assays were designed to improve upon the "classic" tests by excluding the possibility to avoid or escape aversive areas of each maze. The 3-D radial arm maze (3DR) and the 3-D open field test (3Doft) each consist of an open space connected to ambiguous paths toward uncertain escape. This introduces continual motivational conflict, thereby increasing external validity as an anxiety model. But despite this improvement, the revised assays have not caught on. One issue may be that studies to date have not directly compared classic and revised assays in the same animals. To remedy this, we contrasted behavior in a battery of assays (EPM, OFT, 3DR, 3Doft, and a sociability test) in mice defined either genetically by isogenic strain, or environmentally by postnatal experience. Findings indicate that the optimal assay to assess anxiety-like behavior may depend upon grouping variable (e.g. genetic versus environment). We argue that the 3DR may be the most ecologically valid of the anxiety assays tested, while the OFT and 3Doft provided the least useful information. Finally, exposure to multiple assays significantly affected sociability measures, raising concerns for designing and interpreting batteries of behavioral tests in mice.

animal behavior and cognition↗

bioRxiv2022

Neuronal Activity Alters Neuron to OPC Synapses

The mechanisms that drive the timing and specificity of oligodendrocyte myelination during development, or remyelination after injury or immune attack are not well understood. Recent work has shown that oligodendrocyte progenitors receive synapses from neurons, providing a potential mechanism for neuronal-glial communication. We hypothesize that these connections are important both for correct myelination of neurons during development and for myelination during neuronal plasticity. We utilized chemogenetic tools and viral monosynaptic circuit tracing to analyze these neuroglial connections and to examine OPC proliferation, myelination, synapse formation, and neuronal-glial connectivity after increasing or decreasing neuronal activity in vivo. We found that increasing neuronal activity increased OPC activation, but not proliferation. We also found that altering neuronal activity altered neuronal-glial synaptic connections: while it did not impact the total number of neuronal inputs, or the number of inhibitory neuronal inputs, it did alter the number of excitatory neuron to OPC connections. We also found that increasing or decreasing neuronal activity impacted the ratio of excitatory and inhibitory synapses. Our data show that neuronal activity affects OPC activation, neuronal synapse formation onto OPCs, as well as the types of neuronal inputs to OPCs, indicating that neuronal activity is important for OPC circuit composition and function.

neuroscience↗

bioRxiv2019

Phasic signaling in the bed nucleus of the stria terminalis during fear learning predicts within- and across-session cued fear expression

While results from many past studies have implicated the bed nucleus of the stria terminalis (BNST) in mediating the expression of sustained negative affect, recent studies have highlighted a more complex role for BNST that includes aspects of fear learning in addition to defensive responding. As BNST is thought to encode ambiguous or unpredictable threat, it seems plausible that it may be involved in encoding early cued fear learning, especially immediately following a first tone-shock pairing when the CS-US contingency is not fully apparent. To investigate this, we conducted in vivo electrophysiological recording studies to examine neural dynamics of BNST units during cued fear acquisition and recall. We identified two functionally distinct subpopulations of BNST neurons that encode the intertrial interval (ITI) and seem to contribute to within- and across-session fear learning. \"Ramping\" cell activity during cued fear acquisition parallels the increase in freezing expression as mice learn the CS-US contingency, while \"Phasic\" cells encode post-shock (USpost) periods (30 s following encounter with footshock) only during early trials. Importantly, the magnitude of Phasic unit responsivity to the first USpost period predicted not only freezing expression in response to the subsequent CS during acquisition, but also CS freezing evoked 24 hr later during CS retrieval. These findings suggest for the first time that BNST activity may serve as an instructive signal during cued fear learning.

neuroscience↗