Expression and secretion of neurotrophic factors have long been known as a key mechanism of neuroglial interaction in the central nervous system. In addition, several other intrinsic neuroprotective pathways have been described, including those involving small heat shock proteins such as α-crystallins. While initially considered as a purely intracellular mechanism, both αA-crystallins and αB-crystallins have been recently reported to be secreted by glial cells. While an anti-apoptotic effect of such secreted αA-crystallin has been suggested, its regulation and protective potential remain unclear. We recently identified residue threonine 148 (T148) and its phosphorylation as a critical regulator of αA-crystallin intrinsic neuroprotective function. In the current study, we explored how mutation of this residue affected αA-crystallin chaperone function, secretion, and paracrine protective function using primary glial and neuronal cells. After demonstrating the paracrine protective effect of αA-crystallins sec...

Brain-derived neurotrophic factor (BDNF) and its receptor, tropomyosin receptor kinase B (TrkB), are implicit in causing obesity. Mutations that reduce BDNF and TrkB expression are associated with obesity in humans and mice. Recently, it was reported that Bdnf gene deletion in the neurons of the paraventricular hypothalamus (PVH) caused positive energy balance and severe obesity in the form of hyperphagia, impaired adaptive thermogenesis, and decreased energy expenditure. Thus, we hypothesize that activation of these neurons will have the opposite effect and provide an opportunity for long-lasting obesity treatment. To specifically activate BDNF-expressing PVH (PVHBDNF) neurons, we injected Cre-dependent adeno-associated virus (AAV) expressing the excitatory DREADD hM3Dq bilaterally into the PVH of Bdnf2A-Cre/+ knock-in mice and then administered clozapine-N-oxide (CNO). Using this technique, we demonstrated that acute activation of these neurons rapidly decreased normal nocturnal feeding and fasting-induc...

Cisplatin-induced ototoxicity can be partially attributed to excessive reactive oxygen species (ROS) production, and agmatine is well-known for the activation of the phosphoinositide-3-kinase (PI3K)/protein kinase B (AKT) pathway to inhibit ROS production. Whether agmatine could be used to alleviate cisplatin-induced ototoxicity is investigated. Cisplatin-exposed House Ear Institute-Organ of Corti 1 (HEI-OC1) cells and cochlear explants showed increased ROS production detected by 2′,7′-dichlorodihydrofluorescein diacetate (DCFH-DA) staining and decreased cell viability detected by Cell Counting Kit-8 (CCK-8) or Myosin 7a staining, which could be reversed by the agmatine pretreatment. Cisplatin intraperitoneally injected C57BL/6 mice demonstrated damaged auditory function as indicated by distortion products otoacoustic emissions (DPOAEs) and auditory brainstem response (ABR) assays, and trans-tympanically administrated agmatine in the left ears could partly prevent the auditory function loss. Mechanisticall...

The basal ganglia (BG) are crucial for a variety of motor and cognitive functions. Changes induced by persistent low-dopamine (e.g., in Parkinson’s disease; PD) result in aberrant changes in steady-state population activity (β band oscillations) and the transient response of the BG. Typically, a brief cortical stimulation results in a triphasic response in the substantia nigra pars reticulata (SNr; an output of the BG). The properties of the triphasic responses are shaped by dopamine levels. While mechanisms underlying aberrant steady state activity are well studied, it is still unclear which BG interactions are crucial for the aberrant transient responses in the BG. Moreover, it is also unclear whether mechanisms underlying the aberrant changes in steady-state activity and transient response are the same. Here, we used numerical simulations of a network model of BG to identify the key factors that determine the shape of the transient responses. We show that an aberrant transient response of the SNr in the...

When faced with multiple potential movement options, individuals either reach directly to one of the options, or initiate a reach intermediate between the options. It remains unclear why people generate these two types of behaviors. Using the go-before-you-know task (commonly used to study behavior under choice uncertainty) in humans, we examined two key questions. First, do these two types of responses actually reflect distinct movement strategies? If so, the relative desirability (i.e., weighing the success likelihood vs the attainable reward) of the two target options would not need to be computed identically for direct and intermediate reaches. We showed that indeed, when reward and success likelihood differed between the two options, reach direction was preferentially biased toward different directions for direct versus intermediate reaches. Importantly, this suggests that the computation of subjective values depends on the choice of movement strategy. Second, what drives individual differences in how...

Axon guidance receptors such as deleted in colorectal cancer (DCC) contribute to the normal formation of neural circuits, and their mutations can be associated with neural defects. In humans, heterozygous mutations in DCC have been linked to congenital mirror movements, which are involuntary movements on one side of the body that mirror voluntary movements of the opposite side. In mice, obvious hopping phenotypes have been reported for bi-allelic Dcc mutations, while heterozygous mutants have not been closely examined. We hypothesized that a detailed characterization of Dcc heterozygous mice may reveal impaired corticospinal and spinal functions. Anterograde tracing of the Dcc +/− motor cortex revealed a normally projecting corticospinal tract, intracortical microstimulation (ICMS) evoked normal contralateral motor responses, and behavioral tests showed normal skilled forelimb coordination. Gait analyses also showed a normal locomotor pattern and rhythm in adult Dcc +/− mice during treadmill locomotion, ex...

Electron microscopy (EM)-based connectomes provide important insights into how visual circuitry of fruit fly Drosophila computes various visual features, guiding and complementing behavioral and physiological studies. However, connectomic analyses of the lobula, a neuropil putatively dedicated to detecting object-like features, remains underdeveloped, largely because of incomplete data on the inputs to the brain region. Here, we attempted to map the columnar inputs into the Drosophila lobula neuropil by performing connectivity-based and morphology-based clustering on a densely reconstructed connectome dataset. While the dataset mostly lacked visual neuropils other than lobula, which would normally help identify inputs to lobula, our clustering analysis successfully extracted clusters of cells with homogeneous connectivity and morphology, likely representing genuine cell types. We were able to draw a correspondence between the resulting clusters and previously identified cell types, revealing previously und...

θ-Scale coordination of prelimbic medial prefrontal cortex (mPFC) local field potentials (LFPs) and its influence via direct or indirect projections to the ventral hippocampus (vHC) and dorsal hippocampus (dHC) during spatial learning remains poorly understood. We hypothesized that θ frequency coordination dynamics within and between the mPFC, dHC, and vHC would be predetermined by the level of connectivity rather than reflecting differing circuit throughput relationships depending on cognitive demands. Moreover, we hypothesized that coherence levels would not change during learning of a complex spatial avoidance task. Adult male rats were bilaterally implanted with EEG electrodes and LFPs recorded in each structure. Contrary to predictions, θ coherence averaged across “Early” or “Late” training sessions in the mPFC-HC, mPFC-mPFC, and HC-HC increased as a function of task learning. Coherence levels were also highest between the indirectly connected mPFC-dHC circuit, particularly during early training. Alth...

Humans can perform complex movements with speed and agility in the face of constantly changing task demands. To accomplish this, motor plans are adapted to account for errors in our movements because of changes in our body (e.g., growth or injury) or in the environment (e.g., walking on sand vs ice). It has been suggested that adaptation that occurs in response to changes in the state of our body will generalize across different movement contexts and environments, whereas adaptation that occurs with alterations in the external environment will be context-specific. Here, we asked whether the ability to form generalizable versus context-specific motor memories develops during childhood. We performed a cross-sectional study of context-specific locomotor adaptation in 35 children (3–18 years old) and 7 adults (19–31 years old). Subjects first adapted their gait and learned a new walking pattern on a split-belt treadmill, which has two belts that move each leg at a different speed. Then, subjects walked overgro...

Cortical spreading depression (CSD) is a wave of pronounced depolarization of brain tissue accompanied by substantial shifts in ionic concentrations and cellular swelling. Here, we validate a computational framework for modeling electrical potentials, ionic movement, and cellular swelling in brain tissue during CSD. We consider different model variations representing wild-type (WT) or knock-out/knock-down mice and systematically compare the numerical results with reports from a selection of experimental studies. We find that the data for several CSD hallmarks obtained computationally, including wave propagation speed, direct current shift duration, peak in extracellular K+ concentration as well as a pronounced shrinkage of extracellular space (ECS) are well in line with what has previously been observed experimentally. Further, we assess how key model parameters including cellular diffusivity, structural ratios, membrane water and/or K+ permeabilities affect the set of CSD characteristics.