Dr. Ann McKee will describe the emergence of chronic traumatic encephalopathy (CTE) as a distinct disease over the past 20 years.

The refinement of gross motor skills, such as locomotion, during development is conserved across vertebrate species. Our previous work demonstrated, in larval zebrafish, that dopaminergic signaling through the dopamine D2-like family of receptors, specifically the dopamine 4 receptor subtype, was necessary for the developmental transformation of behaviorally relevant locomotor activity from an immature to a mature pattern between 3 and 4 d postfertilization. In this study, we used a complement of tools, including electrophysiology, pharmacology, in vivo calcium imaging, liquid chromatography-mass spectrometry, and quantitative reverse transcription polymerase chain reaction to characterize the functional and molecular mechanisms responsible for this dopaminergic-mediated refinement of spinal locomotor activity. The results demonstrate that the dopamine 4 receptor subtype is functional in, at least, a subset of immature larvae. Further, gene expression of all D2-like receptor subtypes, levels of dopamine, a...

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 ...

Vocal communication is essential for social behavior, yet the distributed brain networks underlying vocal production remain elusive. Male mice produce ultrasonic vocalizations (USVs) during courtship, providing a rodent model for investigating neural circuits underlying innate vocal communication. Here, we used a double-labeling strategy combining genetic activity tagging (TRAP2) and c-Fos immunohistochemistry to generate an unbiased, whole-brain map of neuronal ensembles activated during courtship-induced USV production in adult male mice. By tracking neuronal activity across 25 brain regions during two independent courtship sessions, we identified populations consistently recruited during social vocalization. Quantitative analyses revealed robust activation in the caudal periaqueductal gray, confirming its established role as a hub for vocal motor control. Importantly, correlation analyses between neuronal activity and USV count distinguished regions specifically linked to vocal output from those associa...

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...

Neurons couple to various degrees to the activity level of the local neighboring population whereby strongly coupled “choristers” and weakly coupled “soloists” have been identified as two extremes of a continuous spectrum. At the same time neuronal populations undergo coordinated ON and OFF cortical state activity fluctuations, which are locally modulated by attention. The population coupling of soloists and choristers suggests that soloists should show limited alignment with cortical state fluctuations, while choristers should exhibit profound alignment. To test this, we recorded neurons across cortical layers in macaque areas V1 and V4 ( n  = 2 males), while animals performed a feature-based spatial attention task. As expected, we found a wide range of population coupling strength of neurons. In line with our prediction, coupling of choristers to cortical state changes (ON-OFF transitions) was generally stronger than that of soloists. The strength of population coupling of neurons was similar during spon...

Ischemic stroke, a leading cause of neurological morbidity, is characterized by extensive neuronal injury and a robust inflammatory response. Erbin, a scaffold protein involved in multiple cellular signaling pathways, regulates neuroinflammation and may confer neuroprotection against ischemia–reperfusion (I/R) injury. A mouse model of middle cerebral artery occlusion was utilized to evaluate the neuroprotective role of Erbin. Male mice were allocated into groups receiving either a lentiviral (LV) control vector or LV-mediated Erbin overexpression, followed by I/R injury induction. Neurological function, infarct volume, and expression levels of inflammatory cytokines and mitogen-activated protein kinase (MAPK) signaling proteins were analyzed. Overexpression of Erbin via LV transduction significantly reduced cerebral infarct volume and mitigated neurological impairments post-I/R injury. Furthermore, Erbin overexpression suppressed the phosphorylation of p38 and extracellular signal-regulated kinase in HT22 ...