Biology subjects

Lacefield, C.

Publications and source records attributed to Lacefield, C..

8 recordsLinked to original sources

bioRxiv2025

Safety learning induces postsynaptic potentiation of direct pathway spiny projection neurons in the tail of the striatum

The association of a sensory cue with an outcome is a crucial step in learning to identify safe versus threatening situations. Here we assessed how learned sound-safety association alters neuronal activity in tail of the striatum (TS), where auditory cortical and thalamic inputs converge. Prior to training, foot shock elicited responses by TS direct and indirect pathway spiny projection neurons (SPNs), while sound tones produced no response. However, once the sound association was learned, sound tones strongly activated TS SPNs, even when the animal was under anesthesia. This conditioned auditory response occurred concurrently with alterations of direct pathway SPNs in the TS, including increased responses to cortical and auditory thalamic inputs, increased excitatory response with an enhanced ratio of NMDA to AMPA receptors, decreased responses to inhibitory input, and increased dendritic spines. This convergence of postsynaptic changes provides responses to relevant auditory cues during associative learning. TeaserSound-safety association enhances response to learned sound in striatal neurons via postsynaptic mechanisms

neuroscience↗

bioRxiv2025

Distinct representations of an anxiogenic environment in different cell types of the ventral hippocampus

In addition to its role in episodic memory and spatial navigation, the hippocampus has also been found to influence mood-related disorders such as anxiety and depression. These seemingly distinct roles are consistent with a functional dissociation between the two anatomical poles of the hippocampus: whereas the dorsal portion of the hippocampus in rodents is necessary for spatial tasks, the ventral portion controls affective behaviors. We have recently found that neurons in the ventral, but not dorsal, CA1 area of mice encode anxiety-related information (i.e. are "anxiety cells") in diverse defensive and exploratory behaviors. Still it is unclear how general threat-related information is computed within the hippocampal circuit. In this work, we have examined how distinct hippocampal subregions and cell types encode anxiety-related information by imaging calcium activity in large populations of genetically-defined neurons in the ventral hippocampus while mice explore the elevated plus maze (EPM), a conflict-based anxiety test. We compared the neural encoding of task-related features within the ventral CA1 (vCA1) and ventral dentate gyrus (vDG) regions in order to examine the emergence of anxiety-related activity through the hippocampal circuit. We found that granule cells (vGCs) of the vDG represented similar valence information to neurons in vCA1 in the form of arm-type specific encoding in the EPM, which suggests that encoding of anxiety-related features is already present at this first stage of hippocampal processing. When compared with ventral granule cells (vGCs), ventral mossy cells (vMCs) underlying the DG had stronger spatial encoding and less valence encoding, suggesting that they may be more functionally connected with the highly spatially sensitive dorsal hippocampus. Together these findings will help to understand the encoding of anxiety-related information in the hippocampus and how it relates to neural circuit defects in mood-related disorders.

neuroscience↗

bioRxiv2025

Antidepressants promote developmental-like plasticity through remodeling of extracellular matrix

Antidepressants are widely used to treat mood and anxiety disorders, yet the cellular and molecular mechanisms underlying their therapeutic effects remain poorly understood. Here, we show that the selective serotonin reuptake inhibitor (SSRI) fluoxetine rejuvenates the dentate gyrus (DG) by reactivating a latent developmental plasticity program in mature neurons, which is required for re-engaging critical period-like synaptic remodeling and antidepressant-like behavioral effects. Single nuclei transcriptomic profiling across all hippocampal cell types revealed a strikingly selective response in the DG, where mature neurons re-engaged a developmental-like transcriptional state, an effect distinct from adult neurogenesis. Chronic fluoxetine treatment induced expression of SOX11, a developmental transcription factor involved in neurodevelopment and axonal regeneration that is normally silenced in the adult brain. Reactivation of SOX11 in mature DG neurons was necessary for both the antidepressant-like behavioral effects of fluoxetine and the re-engagement of critical period-like synaptic remodeling. Notably, SOX11 reactivation was also induced by physiological stimuli, including environmental enrichment and peripheral axon regeneration, suggesting that mature neurons retain access to a conserved developmental plasticity program throughout adulthood. We further identified evidence of this form of developmental plasticity in the adult human brain, an effect distinct from adult neurogenesis. At the structural level, fluoxetine remodeled novel extracellular matrix (ECM) structures within the DG distinct from canonical perineuronal nets, and targeted ECM degradation was sufficient to reactivate SOX11 in mature neurons, identifying the ECM as a key regulator of neuronal rejuvenation. Altogether, these findings demonstrate that mature neurons retain an intrinsic capacity to re-engage dormant developmental programs, and that antidepressants harness this regenerative plasticity to drive neural circuit remodeling and antidepressant-like effects.

neuroscience↗

bioRxiv2024

Prefrontal representations of retrospective spatial working memory in a rodent radial maze task

Working memory is the cognitive capacity for temporarily holding information in mind for processing or use. It has been theorized to depend upon executive and mnemonic subcomponents, although the contextual mapping of these subcomponents is not complete. Perturbations of prefrontal cortex (PFC) delay activity disrupt spatial working memory performance in rodent tasks. However, recordings of unperturbed PFC delay activity do not consistently contain mnemonic representations of spatial information in these tasks, calling into question the role that mnemonic PFC representations play in freely-moving spatial working memory. We hypothesized that increasing task complexity might increase the likelihood of mnemonic PFC representation emergence. We therefore used an automated eight-arm radial maze to implement a novel match-to-sample rodent spatial working memory task with seven options on each trial, and recorded calcium activity in PFC neurons during task performance. We found that the delay-phase activity of PFC neurons indeed contained mnemonic representations of spatial information at the population level. These representations were retrospective rather than prospective, and--surprisingly--were more evident on error trials. Together with previous results, these observations suggest that in freely-moving spatial working memory tasks, PFC mnemonic representations emerge to empower deviation from a routine behavioral strategy. Significance StatementPrefrontal cortex (PFC) activity is necessary for optimal performance of freely-moving spatial working memory tasks in rodents. Despite this, PFC representations of retrospective actions or stimuli--one quintessential working memory hallmark--are only variably observed during task delays, complicating our understanding of the PFCs role in spatial working memory. Here, we examine cellular-resolution PFC activity in a high-optionality match-to-sample radial maze task and find retrospective delay representations. Strikingly, these delay representations are more evident in error trials. This suggests that in the freely-moving context, explicit PFC representations of retrospective information support deviations from an entrained behavioral strategy, rather than equally supporting all spatial working memory-based behavior.

animal behavior and cognition↗

bioRxiv2021

Activity in the dorsomedial striatum decreases with improvement in motor coordination

It has been suggested that the dorsomedial striatum (DMS) facilitates the early stages of motor learning for goal-directed actions, whereas at later stages, control is transferred to the dorsolateral striatum (DLS), which enables the motor actions to become a skill or habit. It is unknown whether these striatal regions are simultaneously active while expertise is acquired during skill learning. To address this question, we developed the "treadmill training task" to track changes in mouse locomotor coordination during practice at running that simultaneously provides a means to measure local neuronal activity using photometry. We analyzed body position and paw movement to evaluate changes in motor coordination over practice sessions on the treadmill using DeepLabCut and custom-built code. By correlating improvements in motor coordination during training with simultaneous neuronal calcium activity in the striatum, we found that DMS direct pathway neurons exhibited decreased activity as the mouse gains proficiency at running. In contrast, direct pathway activity in the DLS was similar throughout training and did not correlate with learned skill proficiency. Pharmacological blockade of D1 dopamine receptors in these subregions during task performance confirmed that dopamine neurotransmission in the DMS direct pathway activity is necessary for efficient motor coordination learning, while dopamine signalling in the DLS is important for both coordination learning and maintenance of the acquired skill. These results provide new tools to measure changes in fine motor skills during simultaneous recordings of brain activity, revealing fundamental features of the neuronal substrates of motor learning.

neuroscience↗

bioRxiv2021

3D Neuronal Mitochondrial Morphology in Axons, Dendrites, and Somata of the Aging Mouse Hippocampus

The brains ability to process complex informations relies on the constant supply of energy through aerobic respiration by mitochondria. Neurons contain three anatomically distinct compartments - the soma, dendrites, and projecting axons - which have different energetic and biochemical requirements, as well as different mitochondrial morphologies in cultured systems. Here we apply a quantitative three-dimensional electron microscopy approach to map mitochondrial network morphology and complexity in the mouse brain. We examine three neuronal sub-compartments - the soma, dendrites, myelinated axons - in the dentate gyrus and CA1 of the mouse hippocampus, two subregions with distinct principal cell types and functions. We also establish compartment-specific differences in mitochondrial morphology across these cell types between young and old mice, highlighting differences in age-related morphological recalibrations. Overall, these data define the nature of the neuronal mitochondrial network in the mouse hippocampus, providing a foundation to examine the role of mitochondrial morpho-function in the aging brain.

neuroscience↗

bioRxiv2020

Human Hair Graying is Naturally Reversible and Linked to Stress

Hair graying is a universal hallmark of aging believed to be linked to psychological stress. Here we develop a novel approach to quantitatively profile natural graying events along individual human hair shafts, resulting in a quantifiable physical timescale of hair pigmentation patterns (HPPs). Using this approach, we quantify rare events of white/gray hairs that naturally regain pigmentation within days to weeks, thereby quantitatively defining the reversibility of graying in healthy, unmedicated individuals. Proteomic analysis shows that graying is marked by the upregulation of proteins related to energy metabolism, mitochondria, and antioxidant defenses. Combining hair pigmentation profiling and proteomics at the single hair level, we also report hair graying and its reversal occurring in parallel with behavioral and psychological stressors. A computational simulation suggests a threshold-based mechanism for the temporary reversibility of graying. Quantitatively mapping HPPs in humans provides an opportunity to longitudinally examine the influence of life exposures on biological aging.

cell biology↗

bioRxiv2020

DIY-NAMIC behavior: A high-throughput method to measure complex phenotypes in the homecage

Complex behavioral assessment is becoming increasingly necessary in order to comprehensively assess in vivo manipulations in rodent models. Using operant behavioral paradigms provides rich data sets allowing for the careful analysis of behavioral phenotypes. However, one major limitation in these studies is the expense and work-load that are required using traditional methods. The equipment for commercial operant boxes can be prohibitively expensive, and the daily experimenter effort and mouse costs required for these studies is extensive. Rodents are generally trained on task-specific paradigms for months, tested every day for 5-7 days per week. Additionally, appetitive paradigms usually require food restriction and are also commonly run in the non-active light phase of the rodent circadian rhythm. These limitations make operant behavioral testing especially difficult during adolescence, a time period of interest with regards to the development of adult-like phenotypes and a high-risk period for the development of neuropsychiatric disorders, including those which involve impulsive behavior. In order to address these issues, we developed an automated, inexpensive, open-source method which allows the implementation of most standard operant paradigms in the homecage of rodents in shorter time frames without food restriction, and with much less experimenter effort. All construction and code for the DIY Nautiyal Automated Modular Instrumental Conditioning (DIY-NAMIC) system are open source. We demonstrate their utility here by measuring impulsive behavior in a pharmacology experiment, as well as in adolescent mice.Significance statement Rigorous behavioral assessment is critical to understand the neural basis of neuropsychiatric disorders using animal models. Operant behavioral paradigms provide the ability to measure complex phenotypes, however, traditional methods generally require time-consuming daily training for many weeks. We designed, built, and tested an open-source automated homecage system for appetitive instrumental conditioning that enables testing in shorter timeframes with reduced experimenter effort.Competing Interest StatementThe authors have declared no competing interest.View Full Text

animal behavior and cognition↗