Olfactory anhedonia and heightened aversion to unpleasant odors are well-documented features of depression in humans, yet the neural mechanisms linking chronic stress to altered olfactory perception remain poorly understood. We used the unpredictable chronic mild stress (UCMS) paradigm to examine how chronic stress affects olfactory avoidance behavior and glial cell morphology across multiple olfactory brain regions in male and female mice. UCMS-treated mice showed increased avoidance of aversive odorants in an odorized light/dark box assay, consistent with heightened aversive reactivity to odors following chronic stress. Using immunohistochemistry, we assessed microglial morphology and astrocyte density across six olfactory and limbic brain regions. Chronic stress produced region-specific glial remodeling: astrocyte counts were selectively elevated in the medial amygdala, and microglial process complexity was increased in the anterior olfactory nucleus and anterior piriform cortex. Microglial morphologica...

Aggression may be behaviorally distinguished by reactive or appetitive properties. Here, we use a model of operant aggression administration, in which outbred male CD-1 mice lever press (contingent) or do not lever press (noncontingent) to attack an intruder mouse, to examine behavioral differences in aggression reinforcement. Contingent reinforcement identifies the behavioral and neural basis of appetitive, or rewarding, aggression self-administration, while noncontingent reinforcement isolates reactive, or involuntary, components. Females are not used in this study due to their low propensity to attack. We applied supervised machine-guided behavioral classification and Shapley additive scores (SHAP) to describe differences and similarities in attack behavior features. We find that behavioral sequences of an attack bout are similar whether aggression reinforcement is contingent or noncontingent, though underlying neural mechanisms differ. Fos immunolabeling following operant reinforcement reveals distinct...

Implicit sequence and visuomotor skill learning is important for successful goal-directed behavior in everyday tasks. However, prior research has primarily relied on correlational methods to investigate the underlying neural mechanisms of sequence and visuomotor skill learning. To evaluate the necessary contributions of different motor cortical regions to both types of skill learning, we enrolled 62 neurotypical adults (41 females, 21 males) and delivered spatiotemporally resolved single-pulse transcranial magnetic stimulation (TMS) over either the premotor cortex (PMC) or primary motor cortex (M1) to transiently disrupt activity while participants practiced an implicit motor sequence task. We hypothesized that (1) PMC disruption would preferentially reduce sequence-specific skill acquisition (Experiment 1) and retention (Experiment 2), while (2) M1 disruption would diminish visuomotor skill acquisition and retention but not sequence learning. Our results demonstrated that TMS-based interference over both ...

Neuronal populations connected by gap junctions can be revealed via dye coupling of small molecules like neurobiotin and Lucifer yellow. However, the extent of dye diffusion between neurons varies with connexin subtype, loading method, and neuromodulation. Due to the increasing availability of GCaMP transgenic animals, we explore the possibility of revealing gap junctional coupling using Ca2+ imaging in the motor system of Xenopus laevis tadpole of either sex. Reliable axo-axonal electrical coupling was previously found in excitatory descending interneurons (dINs) using paired recordings but not with neurobiotin dye coupling. Here, we made whole-cell patch–clamp recordings with Ca2+-supplemented intracellular solution to load Ca2+ into GCaMP6-expressing neurons, followed by Ca2+ imaging to detect potential Ca2+ diffusion across coupled neurons. Successful membrane breakthroughs led to transient fluorescence increases in the patched neuron. However, increasing the Ca2+ concentration promoted membrane reseal...

Sensorimotor adaptation depends on implicit recalibration and explicit strategy. These processes are commonly assumed to sum ( A  =  I  +  E ), and this additivity assumption justifies subtractive measurement and informs computational models of motor learning. Recent work has challenged additivity by examining regression slopes between implicit and explicit measures. When slopes deviate from β  = −1, the interpretation has been that the processes are “sub-additive” and fail to sum as expected. Here, we show this reasoning is mistaken. Regression slopes reflect covariance structure: how learning processes relate across individuals. Additivity is a claim about motor output combination: whether learning processes sum within individuals. These are different questions, and regression slopes do not address the latter. We derive the expected slope under subtractive logic and show it equals β  = −1 only when total adaptation is uncorrelated with the measured component. Monte Carlo simulations confirm this benchmar...

Decision-making is a continuous process that manifests as evolving sequences of motor movements while animals navigate the sensory environment. Studying decision-making in a naturalistic setting has been challenging as restrictions are typically imposed on subjects’ motor actions in the laboratory. We utilized a novel paradigm in which animals move freely throughout the decision-making process to examine the sequence and timing of motor actions predictive of decisions. We trained freely moving ferrets (two males, three females), highly visual carnivores, to perform visual discrimination tasks and measured their head position and eye movements to assess the temporal dynamics of heading and saccades during visually guided decisions. We discovered that heading revealed ferrets' “turning time” per trial, signaling their choices, and heading on its own best predicted ferrets' decisions. Ferrets made decisions quickly and decisively, although total trial durations varied across animals. Importantly, initial head...

Animal learning can be analyzed on two timescales: task acquisition across training sessions and motivation fluctuations within training sessions. How do variations in motor and neurophysiologic activity relate to task performance over these timescales? Here, this question was examined in head-fixed mice performing a whisker-based sensory discrimination task. Male mice were trained for 12–14 daily sessions on a go/no-go task, each lasting ∼1 h to capture spontaneous performance fluctuations over minutes. Simultaneous to task performance, “nonperformance variables” were tracked, including wheel running, pupil size, eyelid aperture, and sensory cortical activity. First, motivation states were defined based on performance tendencies over minutes, leading to three state categories: persistent, disengaged, or attentive. Nonperformance variables were found to predict these states independent of task correctness. Then, when further parsing these states by the go/no-go outcomes of hit, miss, false alarm, or correc...

Following a traumatic brain injury (TBI), the neocortex undergoes time-dependent cellular responses including immediate tissue deformation, enhanced excitability, and elevated expression of immediate early genes. However, the spatial extent of early neuronal activity after a focal injury remains unclear. Here we use targeted recombination in active populations reporter mice of both sexes to identify neurons activated in the acute phase following a controlled cortical impact injury applied to the somatosensory neocortex. We find widespread cell activation across large portions of the cortex that extends beyond the astrocytic and microglial responses marking the injury site. Activated cells are predominantly neurons, and few cells colabel with GFAP or IBA1. Our findings reveal that even focal injury engages cortical circuits across large portions of the injured brain, highlighting the importance of considering cortex-wide neuronal dynamics in the early postinjury period and their potential impact on network ...

Dopamine D1 receptor (D1R) signaling in the brain has been strongly implicated in multiple cognitive processes, with D1 agonists known to enhance performance. The development of functionally selective D1 agonists that differentially activate D1R-mediated cAMP versus β-arrestin signaling may offer precision therapy if we understand how signaling bias impacts integrated cognitive processes in complex tasks. We therefore examined the effects of two selective D1 agonists, 2-methyldihydrexidine (2MDHX) and PF-06256142 (PF), on a rodent touchscreen-based Trial-Unique Nonmatching-To-Location task. Primarily assessing both spatial working memory and pattern separation in adult male rats, this behavioral paradigm requires greater cognitive demands to maintain performance throughout the testing session, significantly increasing task complexity. Our results revealed an inverted U-shaped dose response curve for both compounds, aligning with our previously published work, but did not demonstrate marked improvement in t...

With repeated exposure to addictive drugs, there is a shift from drug abuse to drug addiction that is mediated by the transition from goal-directed to habitual control. It is well known that the development of habitual control over behavior relies upon cell-type-specific synaptic changes in both D1 and D2 medium spiny neurons (MSNs) in dorsal striatum. Specifically, habitual behavior is mediated by increased synaptic strength in D1 and D2 MSNs in dorsolateral striatum (DLS), suggesting similar cell-type-specific synaptic changes may underlie the development of habitual cocaine-seeking behavior. However, cell-type-specific synaptic changes have not been evaluated in DLS in this context. Therefore, we trained male rats to self-administer cocaine in a self-administration paradigm that allows for differentiation of goal-directed versus habitual cocaine-seeking behavior. Moreover, we used a viral vector under a D2-specific promoter to fluorescently label D2 MSNs with eYFP in DLS. Evoked excitatory postsynaptic ...