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...

The temporal dynamics of perceptual decisions offer a key window into the cognitive processes contributing to decision-making. Investigating perceptual dynamics in a genetically tractable animal model can facilitate the subsequent unpacking of the underlying neural mechanisms. Here, we investigated the time course as well as fundamental psychophysical constants governing visual perceptual decision-making in freely behaving mice. We did so by analyzing response accuracy against reaction time (RT), i.e., conditional accuracy, in a series of two-alternative forced choice (2-AFC) orientation discrimination tasks in which we varied target size, luminance, duration, and presence of a foil. Our results quantified two distinct stages in the time course of mouse visual decision-making: a “sensory encoding” stage in which conditional accuracy exhibits a classic trade-off with response speed, and a subsequent “short-term memory (STM)-dependent” stage in which conditional accuracy exhibits a classic asymptotic decay f...

Genetic mutations in nitrogen permease regulator-like 2 (NPRL2) are associated with a wide spectrum of familial focal epilepsies, autism, and sudden unexpected death of epileptics (SUDEP), but the mechanisms by which NPRL2 contributes to these effects are not well known. NPRL2 is a requisite subunit of the GAP activity toward Rags 1 (GATOR1) complex, which functions as a negative regulator of mammalian target of rapamycin complex 1 (mTORC1) kinase when intracellular amino acids are low. Here, we show that loss of NPRL2 expression in mouse excitatory glutamatergic neurons causes seizures before death, consistent with SUDEP in humans with epilepsy. Additionally, the absence of NPRL2 expression increases mTORC1-dependent signal transduction and significantly alters amino acid homeostasis in the brain. Loss of NPRL2 reduces dendritic branching and increases the strength of electrically stimulated action potentials (APs) in neurons. The increased AP strength is consistent with elevated expression of epilepsy-li...

Parkinson’s disease (PD) results from a loss of dopaminergic neurons. What triggers the break-down of neuronal signaling, and how this might be compensated, is not understood. The age of onset, progression and symptoms vary between patients, and our understanding of the clinical variability remains incomplete. In this study, we investigate this, by characterizing the dopaminergic landscape in healthy and denervated striatum, using biophysical modeling. Based on currently proposed mechanisms, we model three distinct denervation patterns, and show how this affect the dopaminergic network. Depending on the denervation pattern, we show how local and global differences arise in the activity of striatal neurons. Finally, we use the mathematical formalism to suggest a cellular strategy for maintaining normal dopamine (DA) signaling following neuronal denervation. This strategy is characterized by dual enhancement of both the release and uptake capacity of DA in the remaining neurons. Overall, our results derive a...

The central nucleus of the amygdala (CeA) is involved in the expression of fear and has been implicated in several anxiety disorders. This structure is densely innervated by DAergic projections that impinge on amygdalar neurons expressing various dopamine (DA) receptor subtypes, including D2 receptors (D2Rs). Although various pharmacological approaches have assessed the role of D2Rs in the CeA, the actual participation of postsynaptic D2Rs in the CeA to defensive behaviors remains unclear. Here, we investigated the distribution of D2Rs in the CeA and their role in modifying neuronal activity and fear related behaviors in mice. First, using the mouse reporter strain D2R-EGFP, we verified that D2Rs are present both in neurons of the CeA and in A10 dorsocaudal (A10dc) DAergic neurons that innervate the CeA. Moreover, we showed that pharmacological stimulation of D2Rs increases the activity of protein kinase C (PKC)δ cells present in the CeA, a type of neuron previously associated with reduced defensive behavi...

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...

Disorders of the medial temporal lobe (MTL) adversely affect visual working memory (vWM) performance, including feature binding. It is unclear whether these impairments generalize across visual dimensions or are specifically spatial. To address this issue, we compared performance in two tasks of 13 epilepsy patients, who had undergone a temporal lobectomy, and 15 healthy controls. In the vWM task, participants recalled the color of one of two polygons, previously displayed side by side. At recall, a location or shape probe identified the target. In the perceptual task, participants estimated the centroid of three visible disks. Patients recalled the target color less accurately than healthy controls because they frequently swapped the nontarget with the target color. Moreover, healthy controls and right temporal lobectomy patients made more swap errors following shape than space probes. Left temporal lobectomy patients, showed the opposite pattern of errors instead. Patients and controls performed similarl...

The perirhinal cortex (PER) and postrhinal cortex (POR) in the medial temporal lobe are commonly described as two distinct systems that process nonspatial and spatial information, respectively. Recent findings suggest that the two regions exhibit functional overlap when processing stimulus information, especially when associative responses are required in goal-directed behavior. However, we lack the neural correlates of this. In the current study, we recorded spiking activities for single units of the PER and POR as rats were required to choose a response associated with the identity of a visual object or scene stimulus. We found that similar proportions of cells fired selectively for either scene or object between the two regions. In the PER and POR, response-selective neurons showed higher contrast for different responses than stimulus-selective cells did for stimuli. More cells fired selectively for specific choice response in the POR than in the PER. The differential firing patterns of the PER and POR ...

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...