Alcohol dependence can result in long-lasting deficits to decision-making and action control. Neurobiological investigations have identified orbitofrontal cortex (OFC) as important for outcome-related contributions to goal-directed actions during decision-making. Prior work has shown that alcohol dependence induces long-lasting changes to OFC function that persist into protracted withdrawal and disrupts goal-directed control over actions. However, it is unclear whether these changes in function alter representation of action and outcome-related neural activity in OFC. Here, we used the well-validated chronic intermittent ethanol exposure and withdrawal procedure (CIE) to model alcohol dependence in mice and performed in vivo extracellular recordings during an instrumental task in which lever-press actions made for a food outcome. We found alcohol dependence disrupted goal-directed action control and increased OFC activity associated with lever-pressing, but decreased OFC activity during outcome-related epo...

Sleep spindles are intermittent bursts of 11-15 Hz electroencephalogram (EEG) waves that occur during non-rapid eye movement (NREM) sleep. Spindles are believed to help maintain sleep and to play a role in sleep dependent memory consolidation. Here we applied an automated sleep spindle detection program to our large longitudinal sleep EEG dataset (98 human subjects, 6-18 y, >2000 uninterrupted nights) to evaluate maturational trends in spindle wave frequency, density, amplitude, and duration. This large dataset enabled us to apply non-linear as well as linear age models, thereby extending the findings of prior cross-sectional studies that used linear models. We found that spindle wave frequency increased with remarkable linearity across the age range. Central spindle density increased nonlinearly to a peak at age 15.1 years. Central spindle wave amplitude declined in a sigmoidal pattern with the age of fastest decline at 13.5 years. Spindle duration decreased linearly with age. Of the four measures, only s...

Microglia, the resident immune cells of the CNS, have emerged as key regulators of neural precursor cell activity in the adult brain. However, the microglial-derived factors that mediate these effects remain largely unknown. In the present study, we investigated a role for microglial brain-derived neurotrophic factor (BDNF), a neurotrophic factor with well-known effects on neuronal survival and plasticity. Surprisingly, we found that selective genetic ablation of BDNF from microglia increased the production of newborn neurons under both physiological and inflammatory conditions (e.g. LPS-induced infection and traumatic brain injury). Genetic ablation of BDNF from microglia otherwise also interfered with self-renewal/proliferation, reducing their overall density. In conclusion, we identify microglial BDNF as an important factor regulating microglia population dynamics and states, which in turn influences neurogenesis under both homeostatic and pathological conditions. SIGNIFICANCE STATEMENT (1) Microglia...

Mammalian orienting behaviour consists of coordinated movements of the eyes, head, pinnae, vibrissae, or body to attend to an external stimulus. The present study aimed to develop a novel operant task using a touch-screen system to measure spatial attention. In this task, rats were trained to nose-poke a light stimulus presented in one of three locations. The stimulus was presented more frequently in the center location to develop spatial attention bias towards the center stimulus. Changes in orienting responses were detected by measuring the animals' response accuracy and latency to stimuli at the lateral locations, following reversible unilateral chemogenetic inactivation of the superior colliculus (SC). Additionally, spontaneous turning and rotation behaviour was measured using an open field test (OFT). Our results show that right SC inactivation significantly increased the whole body turn angle in the OFT, in line with previous literature that indicated an ipsiversive orientating bias and the presence ...

Operant behavior procedures often rely on visual stimuli to cue the initiation or secession of a response, and to provide a means for discriminating between two or more simultaneously available responses. While primate and human studies typically use LCD or OLED monitors and touch screens, rodent studies use a variety of methods to present visual cues ranging from traditional incandescent light bulbs, single LEDs, and, more recently, touch screen monitors. Commercially available systems for visual stimulus presentation are costly, challenging to customize, and are typically closed source. We developed an open-source, highly-modifiable visual stimulus presentation platform that can be combined with a 3D-printed operant response device. The device uses an eight by eight matrix of LEDs, and can be expanded to control much larger LED matrices. Implementing the platform is low-cost (<$70 USD per device in the year 2020). Using the platform, we trained rats to make nosepoke responses and discriminate between two...

Circuit compensation is often observed in patients with acute ischemic stroke, suggesting the importance of the interaction between brain regions. Also, contextual fear memory is an association between multisensory contexts and fearful stimuli, for which the interaction between the hippocampus and the amygdala is believed to be critical. To understand how focal ischemia in one region could influence the other region, we used a modified photo-thrombosis to induce focal ischemia in the hippocampus or the amygdala or both in freely-moving rats. We found that the learning curve and short-term memory were not affected in the rats although focal ischemia was induced 5 hrs before learning in either the hippocampus or the amygdala; these were impaired by the induction of ischemia in both the regions. Furthermore, the learning curve and short-term memory were impaired when ischemia was induced 24 hrs before learning in either the hippocampus or the amygdala when the synaptic transmission was altered in one region d...

Music's ability to induce feelings of pleasure has been the subject of intense neuroscientific research lately. Prior neuroimaging studies have shown that music-induced pleasure engages cortico-striatal circuits related to the anticipation and receipt of biologically relevant rewards/incentives, but these reports are necessarily correlational. Here, we studied both the causal role of this circuitry and its temporal dynamics by applying Transcranial Magnetic Stimulation (TMS) over the left dorsolateral prefrontal cortex combined with functional Magnetic Resonance Imaging (fMRI) in 17 male and female participants. Behaviorally, we found that, in accord with previous findings, excitation of fronto-striatal pathways enhanced subjective reports of music-induced pleasure and motivation; whereas inhibition of the same circuitry led to the reduction of both. fMRI activity patterns indicated that these behavioral changes were driven by bidirectional TMS-induced alteration of fronto-striatal function. Specifically, ...

With the advent of tools for recording and manipulating activity with high spatiotemporal resolution in defined neural circuits in behaving animals, behavioral neuroscience is now tasked with establishing field-wide standards for implementing and interpreting these powerful approaches. Theoretical frameworks for what constitute proof of fundamental neurobiological principles is an ongoing and frequently debated topic. On the other hand, standardizing interpretation of individual experimental findings to avoid spurious conclusions in practice has received less attention. Even within subfields, similar assays are often used to support widely disparate conclusions which in part has contributed to a slew of studies claiming highly specified functions for cell-types and circuits which are often in direct disagreement with one another. In this opinion piece, we discuss common pitfalls in design and interpretation of approaches for recording or manipulating neural activity in animal models of motivated behavior. ...

GABAergic projections neurons of the substantia nigra reticulata (SNr), through an extensive network of dendritic arbors and axon collaterals, provide robust inhibitory input to neighboring dopaminergic neurons in the substantia nigra compacta (SNc). Angiotensin-II (Ang-II) receptor signaling increases SNc dopaminergic neuronal sensitivity to insult, thus rendering these cells susceptible to dysfunction and destruction. However, the mechanisms by which Ang-II regulates SNc dopaminergic neuronal activity are unclear. Given the complex relationship between SN dopaminergic and GABAergic neurons, we hypothesized that Ang-II could regulate SNc dopaminergic neuronal activity directly and indirectly by modulating SNr GABAergic neurotransmission. Herein, using transgenic mice, slice electrophysiology, and optogenetics, we provide evidence of an AT1 receptor-mediated signaling mechanism in SNr GABAergic neurons where Ang-II suppresses electrically-evoked neuronal output by facilitating postsynaptic GABAA receptors ...

The rodent hippocampus generates new neurons throughout life. This process, named adult hippocampal neurogenesis (AHN), is a striking form of neural plasticity that occurs in the brains of numerous mammalian species. Direct evidence of adult neurogenesis in humans has remained elusive, although the occurrence of this phenomenon in the human dentate gyrus has been demonstrated in seminal studies and recent research that have applied distinct approaches to birthdate newly generated neurons and to validate markers of adult-born neurons. Our data point to the persistence of AHN until the 10th decade of human life, as well as to marked impairments in this process in patients with Alzheimer's disease. Moreover, our work demonstrates that the methods used to process and analyze postmortem human brain samples can limit the detection of various markers of AHN to the point of making them undetectable. In this Dual Perspectives article, we highlight the critical methodological aspects that should be strictly controll...