Dopamine neurons switch from tonic pacemaker activity to high-frequency bursts in response to salient stimuli. These bursts lead to superlinear increases in dopamine release, and the degree of this increase is highly dependent on firing frequency. The superlinearity and frequency-dependence of dopamine release implicates short-term plasticity processes. The presynaptic Ca2+-sensor synaptotagmin-7 (SYT7) has suitable properties to mediate such short-term plasticity and has been implicated in regulating dopamine release from somatodendritic compartments . Here we use a genetically-encoded dopamine sensor and whole-cell electrophysiology in Syt7 knockout mice to determine how SYT7 contributes to both axonal and somatodendritic dopamine release. We find that SYT7 mediates a hidden component of facilitation of release from dopamine terminals that can be unmasked by lowering initial release probability, or by pre-depressing synapses with low-frequency stimulation. Depletion of SYT7 increased short-term depressio...

In the field of behavioral neuroscience, the classification and scoring of animal behavior play pivotal roles in the quantification and interpretation of complex behaviors displayed by animals. Traditional methods have relied on video examination by investigators, which is labor-intensive and susceptible to bias. To address these challenges, research efforts have focused on computational methods and image-processing algorithms for automated behavioral classification. Two primary approaches have emerged: marker- and markerless-based tracking systems. In this study, we showcase the utility of “Augmented Reality University of Cordoba” (ArUco) markers as a marker-based tracking approach for assessing rat engagement during a nose-poking go/no-go behavioral task. In addition, we introduce a two-state engagement model based on ArUco marker tracking data that can be analyzed with a rectangular kernel convolution to identify critical transition points between states of engagement and distraction. In this study, we ...

The subependymal zone (SEZ), also known as the subventricular zone (SVZ), constitutes a neurogenic niche that persists during post-natal life. In humans, the neurogenic potential of the SEZ declines after the first year of life. However, studies discovering markers of stem and progenitor cells highlight the neurogenic capacity of progenitors in the adult human SEZ, with increased neurogenic activity occurring under pathological conditions. In the present study, the complete cellular niche of the adult human SEZ was characterized by single-nucleus RNA sequencing, and compared between 4 youth (age 16-22) and 4 middle-aged adults (age 44-53). We identified 11 cellular clusters including clusters expressing marker genes for neural stem cells (NSCs), neuroblasts, immature neurons and oligodendrocyte progenitor cells. The relative abundance of NSC and neuroblast clusters did not differ between the two age groups, indicating that the pool of SEZ NSCs does not decline in this age range. The relative abundance of o...

We often need to decide whether the object we look at is also the object we look for. When we look for one specific object, this process can be facilitated by feature-based attention. However, when we look for many objects at the same time (e.g., the products on our shopping list) such a strategy may no longer be possible, as research has shown that we can actively prepare to detect only one or two objects at a time. Therefore, looking for multiple objects additionally requires long-term memory search, slowing down decision making. Interestingly, however, previous research has shown that distractor objects can be efficiently rejected during memory search when they are from a different category than the items in the memory set. Here, using EEG, we show that this efficiency is supported by top-down attention at the category level. In Experiment 1, human participants (both sexes) performed a memory search task on individually presented objects from different categories, most of which were distractors. We obse...

Cypin (cytosolic postsynaptic density protein 95 interactor) is the primary guanine deaminase (GDA) in the central nervous system (CNS), promoting the metabolism of guanine to xanthine, an important reaction in the purine salvage pathway. Activation of the purine salvage pathway leads to the production of uric acid (UA). UA has paradoxical effects, specifically in the context of CNS injury as it confers neuroprotection, but it also promotes pain. Since neuropathic pain is a comorbidity associated with spinal cord injury (SCI), we postulated that small molecule cypin inhibitor B9 treatment could attenuate SCI-induced neuropathic pain, potentially by interfering with UA production. However, we also considered that this treatment could hinder the neuroprotective effects of UA, and in doing so, exacerbate SCI outcomes. To address our hypothesis, we induced a moderate mid-thoracic contusion SCI in female mice and assessed whether transient intrathecal administration of B9, starting at 1 day post injury (pi) unt...

High-density neural devices are now offering the possibility to record from neuronal populations in vivo at unprecedented scale. However, the mechanical drifts often observed in these recordings are currently a major issue for “spike sorting,” an essential analysis step to identify the activity of single neurons from extracellular signals. Although several strategies have been proposed to compensate for such drifts, the lack of proper benchmarks makes it hard to assess the quality and effectiveness of motion correction. In this paper, we present a benchmark study to precisely and quantitatively evaluate the performance of several state-of-the-art motion correction algorithms introduced in the literature. Using simulated recordings with induced drifts, we dissect the origins of the errors performed while applying a motion correction algorithm as a preprocessing step in the spike sorting pipeline. We show how important it is to properly estimate the positions of the neurons from extracellular traces in order...

An important aspect of motor function is our ability to rapidly generate goal-directed corrections for disturbances to the limb or behavioral goal. The primary motor cortex (M1) is a key region involved in processing feedback for rapid motor corrections, yet we know little about how M1 circuits are recruited by different sources of sensory feedback to make rapid corrections. We trained two male monkeys ( Macaca mulatta ) to make goal-directed reaches and on random trials introduced different sensory errors by either jumping the visual location of the goal (goal jump), jumping the visual location of the hand (cursor jump), or applying a mechanical load to displace the hand (proprioceptive feedback). Sensory perturbations evoked a broad response in M1 with ∼73% of neurons ( n  = 257) responding to at least one of the sensory perturbations. Feedback responses were also similar as response ranges between the goal and cursor jumps were highly correlated (range of r  = [0.91, 0.97]) as were the response ranges b...

Impulsive action and risk-related decision-making (RDM) are two facets of impulsivity linked to a hyperdopaminergic release in the striatum and an increased propensity to cocaine intake. We previously showed that with repeated cocaine exposure, this initial hyperdopaminergic release is blunted in impulsive animals, potentially signaling drug-induced tolerance. Whether such dopaminergic dynamics involve changes in dopamine (DA) synthesis as a function of impulsivity is currently unknown. Here, we investigated the predictive value of DA synthesis for impulsive action, RDM, and the propensity to take cocaine in a rat model of vulnerability to cocaine abuse. Additionally, we assessed the effects of cocaine intake on these variables. Rats were tested sequentially in the rat Gambling Task (rGT) and were scanned with positron emission tomography and [18F]-FDOPA to respectively assess both impulsivity facets and striatal DA synthesis before and after cocaine self-administration (SA). Our results revealed that base...

Alzheimer’s disease (AD) is the most common form of dementia and results in neurodegeneration and cognitive impairment. White matter (WM) is affected in AD and has implications for neural circuitry and cognitive function. The trajectory of these changes across age, however, is still not well understood, especially at earlier stages in life. To address this, we used the AppNL-G-F/NL-G-F knock-in (APPKI) mouse model that harbors a single copy knock-in of the human amyloid precursor protein ( APP ) gene with three familial AD mutations. We performed in vivo diffusion tensor imaging (DTI) to study how the structural properties of the brain change across age in the context of AD. In late age APPKI mice, we observed reduced fractional anisotropy (FA), a proxy of WM integrity, in multiple brain regions, including the hippocampus, anterior commissure (AC), neocortex, and hypothalamus. At the cellular level, we observed greater numbers of oligodendrocytes in middle age (prior to observations in DTI) in both the AC,...

The olivocerebellar system, which is critical for sensorimotor performance and learning, functions through modules with feedback loops. The main feedback to the inferior olive comes from the cerebellar nuclei (CN), which are predominantly GABAergic and contralateral. However, for the subnucleus d of the caudomedial accessory olive (cdMAO), a crucial region for oculomotor and upper body movements, the source of GABAergic input has yet to be identified. Here, we demonstrate the existence of a disynaptic inhibitory projection from the medial CN (MCN) to the cdMAO via the superior colliculus (SC) by exploiting retrograde, anterograde, and transsynaptic viral tracing at the light microscopic level as well as anterograde classical and viral tracing combined with immunocytochemistry at the electron microscopic level. Retrograde tracing in Gad2-Cre mice reveals that the cdMAO receives GABAergic input from the contralateral SC. Anterograde transsynaptic tracing uncovered that the SC neurons receiving input from the...