Biology subjects

Sicher, A. R.

Publications and source records attributed to Sicher, A. R..

6 recordsLinked to original sources

bioRxiv2026

Prolonged developmental programming of somatostatin neurons defines adolescent remodeling of the prelimbic, but not barrel, cortex

Higher order association cortices like the prefrontal cortex (PFC) mature over a longer developmental window than sensory cortices, but whether genetically defined interneuron populations follow this region-wide delayed trajectory remains unclear. We compared the postnatal development of somatostatin-expressing interneurons in a higher-order cortical region (prelimbic cortex; PLC) and a sensory cortical region (somatosensory barrel cortex; S1BF) across adolescence using complementary structural, electrophysiological, and circuit analyses. We found that the maturation of SST neurons within these two cortical regions differs across time. S1BF SST neurons exhibited relatively linear maturation, whereas PLC SST neurons underwent continued dendritic remodeling, nonlinear intrinsic maturation, and age-dependent refinement of inhibitory output onto pyramidal neurons. Multivariate analyses likewise supported a more linear developmental trajectory in S1BF and a more prolonged, heterogeneous trajectory in PLC. This suggests divergent maturation of the PLC and S1BF and supports a broader, longer window of critical cellular plasticity in the PLC than in sensory cortices. Together, this reflects an extended developmental program at the level of a genetically defined inhibitory cell type. Because SST neurons are positioned to regulate pyramidal neuron output via control of dendritic integration, their delayed maturation is a crucial reflection of overall circuit function. These findings provide a cellular framework for the prolonged plasticity and developmental vulnerability known to be characteristic of adolescent prelimbic cortex. Significance statementWithin the brain, higher order association cortex remains plastic long after sensory cortex has matured, but the cellular basis for this prolonged developmental window has remained unknown. We find that developmental timing is encoded within genetically defined microcircuits. Prelimbic somatostatin circuits continue to remodel after sensory somatostatin circuits have largely stabilized through changes in cell shape, action potential firing dynamics, and inhibitory signaling. This work points to a specific prelimbic inhibitory cell type that matures more slowly, and less linearly, than its counterparts in other brain regions, and may help explain why prelimbic circuits remain vulnerable during adolescence, representing a biological substrate for extended adolescent remodeling in prelimbic cortex, and potentially the overall extensive flexibility, but also cognitive susceptibility, seen during adolescence.

neuroscience↗

bioRxiv2026

Old mice fail to integrate a memory update into an existing hippocampal engram.

Existing memories can be updated by the presentation of new information during memory retrieval. Memory updating is impaired with age, and recent reports indicate this process is more susceptible to age-related impairments than the formation of new memories. However, the neuronal mechanisms underlying age-related updating impairments are unknown. Here, we investigated how memory engrams within the dorsal hippocampus encode a memory update in the young and old brain. We found that old mice tended to re-engage a smaller proportion of the original memory engram during the update session and chemogenetically increasing the activation of this engram alleviated age-related updating deficits. A range of therapeutically relevant behavioral and pharmacological approaches promoting re-engagement of the training engram also improved memory updating in old mice. Together, these results identify a novel mechanism by which memory updating is impaired with age and expand our understanding of how the brain organizes related information.

neuroscience↗

bioRxiv2024

Voluntary adolescent alcohol exposure does not increase adulthood consumption of alcohol in multiple mouse and rat models

Adolescence is a period of increased risk taking, including increased alcohol and drug use. Multiple clinical studies report a positive relationship between adolescent alcohol consumption and risk of developing an alcohol use disorder (AUD) in adulthood. However, few preclinical studies have attempted to tease apart the biological contributions of adolescent alcohol exposure, independent of other social, environmental, and stress factors, and studies that have been conducted show mixed results. Here we use several adolescent voluntary consumption of alcohol models, conducted across four labs in three institutes and with two rodent species, to investigate the ramifications of adolescent alcohol consumption on adulthood alcohol consumption in controlled, pre-clinical environments. We consistently demonstrate a lack of robust increases in adulthood alcohol consumption. This work highlights that risks seen in both human datasets and other murine drinking models may be due to unique social and environmental factors - some of which may be unique to humans. HIGHLIGHTSO_LIAdolescent drinking-in-the-dark (DID) binge drinking does not increase adulthood consumption in a DID model or a two bottle choice model in male and female SST-Cre:Ai9 mice C_LIO_LIAdolescent pair-housed intermittent access consumption of alcohol does not increase adulthood consumption in an identical adulthood model in male and female C57BL/6J mice C_LIO_LIAdolescent intermittent access to alcohol does not increase adulthood consumption in male and female Wistar or Fischer 344 rats C_LIO_LIThese complementary datasets across murine models, labs and institutions highlight the need to consider human social factors as well as biological factors C_LI

neuroscience↗

bioRxiv2024

MODERATE ALCOHOL CONSUMPTION INDUCES LASTING IMPACTS ON PREFRONTAL CORTICAL SIGNALING IN MICE

Both alcohol use disorder (AUD) and Alzheimers Disease and Related Dementias (ADRD) appear to include disruption in the balance of excitation and inhibition in the cortex, but their potential interactions are unclear. We examined the effect of moderate voluntary binge alcohol consumption on the aged, pre-disease neuronal environment by measuring intrinsic excitability and spontaneous neurotransmission on prefrontal cortical pyramidal (excitatory, glutamatergic) and non-pyramidal (inhibitory, GABAergic) neurons following a prolonged period of abstinence from alcohol in mice. Results highlight that binge alcohol consumption has lasting impacts on the electrophysiological properties of prefrontal cortical neurons. A profound increase in excitatory events onto layer 2/3 non-pyramidal neurons following alcohol consumption was seen, along with altered intrinsic excitability of pyramidal neurons, which could have a range of effects on Alzheimers Disease progression in humans. These results indicate that moderate voluntary alcohol influences the pre-disease environment in aging and highlight the need for further mechanistic investigation into this risk factor. HIGHLIGHTSO_LIModerate voluntary alcohol consumption leads to disruption of prefrontal cortical signaling at protracted ages in both male and female mice C_LIO_LIExcitatory glutamatergic events onto prelimbic cortex GABAergic neurons, but not pyramidal neurons, are increased 6 months following alcohol exposure C_LIO_LIBoth pyramidal neurons and GABAergic neurons show altered intrinsic excitability 6 months following alcohol exposure C_LI

neuroscience↗

bioRxiv2022

Adolescent binge drinking leads to long lasting changes in cortical microcircuits

Adolescent drug consumption has increased risks to the individual compared to consumption in adulthood, due to the likelihood of long-term and permanent behavioral and neurological adaptations. However, little is known about how adolescent alcohol consumption influences the maturation and trajectory of cortical circuit development. Here, we explore the consequences of adolescent binge drinking on somatostatin (SST) neuronal function in superficial layers of the prelimbic (PL) cortex in male and female SST-Ai9 mice. We find that adolescent drinking-in-the-dark (DID) produces sex-dependent increases in intrinsic excitability of SST neurons, with no change in overall SST cell number, persisting well into adulthood. While we did not find evidence of altered GABA release from SST neurons onto other neurons within the circuit, we found a complementary reduction in layer II/III pyramidal neuron excitability immediately after binge drinking; however, this hypoexcitability rebounded towards increased pyramidal neuron activity in adulthood in females, suggesting long-term homeostatic adaptations in this circuit. Together, this suggests that binge drinking during key developmental timepoints leads to permanent changes in PL microcircuitry function, which may have broad behavioral implications.

neuroscience↗

bioRxiv2022

Somatostatin Neurons in the Bed Nucleus of the Stria Terminalis Play a Sex-Dependent Role in Binge Drinking

Alcohol use disorder (AUD) is characterized by alcohol use coupled with chronic relapse and involves brain regions including the bed nucleus of the stria terminalis (BNST). Here, we explore whether a subpopulation of BNST neurons, somatostatin (SST) expressing GABAergic neurons, play a role in an animal model of binge-like alcohol consumption, the Drinking in the Dark (DID) model. Chemogenetic activation of BNST SST neurons reduced binge alcohol consumption in female but not male SST-Cre mice, while inhibition of these neurons in the same mice had no effect. In addition, chemogenetic activation of these neurons did not cause apparent changes in models of anxiety-like behavior in either sex. Basal SST cell counts and intrinsic excitability of SST neurons were compared to attempt to understand sex differences in DREADD-induced changes in drinking, and while males had a greater number of BNST SST neurons, this effect went away when normalizing for total BNST volume. Together, these results suggest SST neurons in the BNST should be further explored as a potential neuronal subtype modulated by AUD, and for their therapeutic potential. HIGHLIGHTSO_LIChemogenetic activation of BNST SST neurons reduces binge drinking in female but not male mice C_LIO_LIChemogenetic activation of these neurons has no effect on anxiety-like behavior in either sex C_LIO_LIElectrophysiology revealed no clear sex differences in intrinsic excitability BNST SST neurons between males and females C_LIO_LIImaging revealed males had greater overall BNST SST cell numbers than females, but this effect could be explained by normalizing for total BNST volume C_LI

neuroscience↗