The consequences of aging can vary dramatically between different brain regions and cell types. In the ventral midbrain, dopaminergic neurons develop physiological deficits with normal aging that likely convey susceptibility to neurodegeneration. While nearby GABAergic neurons are thought to be more resilient, decreased GABA signaling in other areas nonetheless correlates with age-related cognitive decline and the development of degenerative diseases. Here, we used two novel cell type-specific translating ribosome affinity purification models to elucidate the impact of healthy brain aging on the molecular profiles of dopamine and GABA neurons in the ventral midbrain. By analyzing differential gene expression from young adult (7-10 months) and old (21-24 months) mice, we detected commonalities in the aging process in both neuronal types, including increased inflammatory responses and upregulation of pro-survival pathways. Both cell types also showed downregulation of genes involved in s

Recording the spiking activity from subcellular compartments of neurons such as axons and dendrites during mouse behavior with 2-photon calcium imaging is increasingly common yet remains challenging due to low signal-to-noise, inaccurate region-of-interest (ROI) identification, movement artifacts, and difficulty in grouping ROIs from the same neuron. To address these issues, we present a computationally efficient preprocessing pipeline for subcellular signal detection, movement artifact identification, and ROI grouping. For subcellular signal detection, we capture the frequency profile of calcium transient dynamics by applying fast Fourier transform (FFT) on smoothed time-series calcium traces collected from axon ROIs. We then apply bandpass filtering methods (e.g., 0.05–0.12 Hz) to select ROIs that contain frequencies that match the power band of transients. To remove motion artifacts from z -plane movement, we apply principal component analysis on all calcium traces and use a bottom-

From lamprey to monkeys, the organization of the descending control of locomotion is conserved across vertebrates. Reticulospinal neurons (RSNs) form a bottleneck for descending commands, receiving innervation from diencephalic and mesencephalic locomotor centers and providing locomotor drive to spinal motor circuits. Given their optical accessibility in early development, larval zebrafish offer a unique opportunity to study reticulospinal circuitry. In fish, RSNs are few, highly stereotyped, uniquely identifiable, large neurons spanning from the midbrain to the medulla. Classically labeled by tracer dye injections into the spinal cord, recent advances in genetic tools have facilitated the targeted expression of transgenes in diverse brainstem neurons of larval zebrafish. Here, we provide a comparative characterization of four existing and three newly established transgenic lines in larval zebrafish. We determine which identified neurons are consistently labeled and offer projection-sp

Cell shape is crucial to cell function, particularly in neurons. The cross-sectional diameter, also known as caliber, of axons and dendrites is an important parameter of neuron shape, best appreciated for its influence on the speed of action potential propagation. Many studies of axon caliber focus on cell-wide regulation and assume that caliber is static. Here, we have characterized local variation and dynamics of axon caliber in vivo using the peripheral axons of zebrafish touch-sensing neurons at embryonic stages, prior to sex determination. To obtain absolute measurements of caliber in vivo, we paired sparse membrane labeling with super-resolution microscopy of neurons in live fish. We observed that axon segments had varicose or “pearled” morphologies and thus vary in caliber along their length, consistent with reports from mammalian systems. Sister axon segments originating from the most proximal branch point in the axon arbor had average calibers that were uncorrelated with each

Pavlovian conditioning tasks have been used to identify the neural systems involved with learning cue–outcome relationships. In delay conditioning, the conditioned stimulus (CS) overlaps or co-terminates with the unconditioned stimulus (US). Prior studies demonstrate that dopamine in the nucleus accumbens (NAc) regulates behavioral responding during delay conditioning. Furthermore, the dopamine response to the CS reflects the relative value of the upcoming reward in these tasks. In contrast to delay conditioning, trace conditioning involves a “trace” period separating the end of the CS and the US delivery. While dopamine has been implicated in trace conditioning, no studies have examined how NAc dopamine responds to reward-related stimuli in these tasks. Here, we developed a within-subject trace conditioning task where distinct CSs signaled either a short trace period (5 s) or a long trace period (55 s) prior to food reward delivery. Male rats exhibited greater conditioned responding a

The medial prefrontal cortex (mPFC) is thought to play a central role in human social perception, cognition, and behavior. In adults, the mPFC is involved in representing and interpreting the mental states in self and others. Developmental research using neuroimaging techniques like functional near-infrared spectroscopy and functional magnetic resonance imaging has begun to extend these findings into infancy. Novel evidence reviewed in this opinion demonstrates that infant mPFC (1) plays a specialized, proactive, and evaluative role in social perception, (2) is involved in connecting with other minds while interacting and when watching other minds interact, and (3) predicts overt social behavior beyond infancy. These findings suggest that, from early in human ontogeny, the mPFC plays a multifaceted role in social perception, cognition, and behavior.

Motor skill learning enables organisms to interact effectively with their environment, relying on neural mechanisms that integrate sensory feedback with motor output. While sensory feedback, such as auditory cues linked to motor actions, enhances motor performance in humans, its mechanism of action is poorly understood. Developing a reliable animal model of augmented motor skill learning is crucial to begin dissecting the biological systems that underpin this enhancement. We hypothesized that continuous auditory feedback during a motor task would promote complex motor skill acquisition in mice. We developed a closed-loop system using DeepLabCut for real-time markerless tracking of mouse forepaw movements with high processing speed and low latency. By encoding forepaw movements into auditory tones of different frequencies, mice received continuous auditory feedback during a reaching task requiring vertical displacement of the left forepaw to a target. Adult mice were trained over 4 d wi

Distinct frontal regions make dissociable contributions to rule-guided decision-making, including the ability to learn and exploit associations between abstract rules and reward value, maintain those rules in memory, and evaluate choice outcomes. Value-based learning can be quantified using reinforcement learning (RL) models predicting optimal trial-wise choices and estimating learning rates, which can then be related to the intact functioning of specific brain areas by combining a modeling approach with lesion-behavioral data. We applied a three-parameter feedback-dependent RL model to behavioral data obtained from macaques with circumscribed lesions to the principal sulcus (PS), anterior cingulate cortex (ACC), orbitofrontal cortex (OFC), superior dorsolateral prefrontal cortex (sdlPFC), and frontopolar cortex (FPC) performing a Wisconsin card sorting task (WCST) analog. Our modeling-based approach identified distinct lesion effects on component cognitive mechanisms contributing to W