The zebrafish, a widely used model in neurobiology, relies on hearing in aquatic environments. Unfortunately, its auditory pathways have mainly been studied in larvae. In this study, we examined the involvement of the anterior tuberal nucleus (AT) in auditory processing in adult zebrafish. Our tract-tracing experiments revealed that the dorsal subdivision of AT is strongly bidirectionally connected to the central nucleus of the torus semicircularis (TSc), a major auditory nucleus in fishes. Immunohistochemical visualization of the ribosomal protein S6 (pS6) phosphorylation to map neural activity in response to auditory stimulation substantiated this finding: the dorsal but not the ventral part of AT responded strongly to auditory stimulation. A similar response to auditory stimulation was present in the TSc but not in the nucleus isthmi, a visual region, which we used as a control for testing if the pS6 activation was specific to the auditory stimulation. We also measured the time course of pS6 phosphoryla...

Parvalbumin-expressing (PV) neurons, classified by their expression of the calcium-binding protein parvalbumin, play crucial roles in the function and plasticity of the lateral habenular nucleus (LHb). This study aimed to deepen our understanding of the LHb by collecting information about the heterogeneity of LHb PV neurons in mice. To achieve this, we investigated the proportions of the transmitter machinery in LHb PV neurons, including GABAergic, glutamatergic, serotonergic, cholinergic, and dopaminergic neurotransmitter markers, using transcriptome analysis, mRNA in situ hybridization chain reaction, and immunohistochemistry. LHb PV neurons comprise three subsets: glutamatergic, GABAergic, and double-positive for glutamatergic and GABAergic machinery. By comparing the percentages of the subsets, we found that the LHb was topographically organized anteroposteriorly; the GABAergic and glutamatergic PV neurons were preferentially distributed in the anterior and posterior LHb, respectively, uncovering the a...

The magnitude of dopamine signals elicited by rewarding events and their predictors is updated when reward value changes. It is actively debated how readily these dopamine signals adapt and whether adaptation aligns with model-free or model-based reinforcement–learning principles. To investigate this, we trained male rats in a pavlovian-conditioning paradigm and measured dopamine release in the nucleus accumbens core in response to food reward (unconditioned stimulus) and reward-predictive conditioned stimuli (CS), both before and after reward devaluation, induced via either sensory-specific or nonspecific satiety. We demonstrate that (1) such devaluation reduces CS-induced dopamine release rapidly, without additional pairing of CS with devalued reward and irrespective of whether the devaluation was sensory-specific or nonspecific. In contrast, (2) reward devaluation did not decrease food reward-induced dopamine release. Surprisingly, (3) postdevaluation reconditioning, by additional pairing of CS with dev...

Treatment of Alzheimer's disease by targeting the antiamyloid beta (Aβ) peptide with immunotherapy has led to Food and Drug Administration approval of several new Aβ monoclonal antibodies. These approvals have come with restrictions, but the uptake of these new therapies in the clinic is expected to increase rapidly, at least in the USA. Hailed as a “breakthrough” by some, there has been stiff countercommentary questioning both safety and efficacy. The authors of this piece have been among those most concerned about the wisdom of releasing these drugs for clinical use. We note that the debate has been thus far largely confined to the clinical literature. With this Social Issues commentary, the authors hope to bring the basic science research community into the discussion. In 2021, despite investing tens of billions of research dollars, the field of Alzheimer's disease (AD) research was struggling. Since the approval of memantine in 2003 and the extension of donepezil for the treatment of severe AD in 2006...

CRISPR/Cas9 gene editing represents an exciting avenue to study genes of unknown function and can be combined with genetically encoded tools such as fluorescent proteins, channelrhodopsins, DREADDs, and various biosensors to more deeply probe the function of these genes in different cell types. However, current strategies to also manipulate or visualize edited cells are challenging due to the large size of Cas9 proteins and the limited packaging capacity of adeno-associated viruses (AAVs). To overcome these constraints, we developed an alternative gene editing strategy using a single AAV vector and mouse lines that express Cre-dependent Cas9 to achieve efficient cell-type specific editing across the nervous system. Expressing Cre-dependent Cas9 from a genomic locus affords space to package guide RNAs for gene editing together with Cre-dependent, genetically encoded tools to manipulate, map, or monitor neurons using a single virus. We validated this strategy with three common tools in neuroscience: ChRonos,...

The role of gamma rhythm (30–80 Hz) in visual processing is debated; stimuli like gratings and hue patches generate strong gamma, but many natural images do not. Could image gamma responses be predicted by approximating images as gratings or hue patches? Surprisingly, this question remains unanswered, since the joint dependence of gamma on multiple features is poorly understood. We recorded local field potentials and electrocorticogram from two female monkeys while presenting natural images and parametric stimuli varying along several feature dimensions. Gamma responses to different grating/hue features were separable, allowing for a multiplicative model based on individual features. By fitting a hue patch to the image around the receptive field, this simple model could predict gamma responses to chromatic images across scales with reasonably high accuracy. Our results provide a simple “baseline” model to predict gamma from local image properties, against which more complex models of natural vision can be ...

Brain activity implies the orchestrated functioning of interconnected brain regions. Typical in vitro models aim to mimic the brain using single human pluripotent stem cell-derived neuronal networks. However, the field is constantly evolving to model brain functions more accurately through the use of new paradigms, e.g., brain-on-a-chip models with compartmentalized structures and integrated sensors. These methods create novel data requiring more complex analysis approaches. The previously introduced circular tripartite network concept models the connectivity between spatially diverse neuronal structures. The model consists of a microfluidic device allowing axonal connectivity between separated neuronal networks with an embedded microelectrode array to record both local and global electrophysiological activity patterns in the closed circuitry. The existing tools are suboptimal for the analysis of the data produced with this model. Here, we introduce advanced tools for synchronization and functional connect...

Chronic neuropathic pain can result from nervous system injury and can persist in the absence of external stimuli. Although ongoing pain characterizes the disorder, in many individuals, the intensity of this ongoing pain fluctuates dramatically. Previously, it was identified that functional magnetic resonance imaging signal covariations between the midbrain periaqueductal gray (PAG) matter, rostral ventromedial medulla (RVM), and spinal trigeminal nucleus are associated with moment-to-moment fluctuations in pain intensity in individuals with painful trigeminal neuropathy (PTN). Since this brainstem circuit is modulated by higher brain input, we sought to determine which cortical sites might be influencing this brainstem network during spontaneous fluctuations in pain intensity. Over 12 min, we recorded the ongoing pain intensity in 24 PTN participants and classified them as fluctuating ( n  = 13) or stable ( n  = 11). Using a PAG seed, we identified connections between the PAG and emotional-affective sites...

Quantifying and analyzing licking behavior can offer valuable insights into fundamental neurobiological mechanisms controlling animal consummatory behaviors. Lickometers are typically based on electrical properties, a strategy that comes with limitations, including susceptibility to electrical interference and generation of electrical disturbances in electrophysiological measurements. While optical lickometers offer an alternative method to measure licks and quantify fluid intake in animals, they are prone to false readings and susceptibility to outside light sources. To overcome this problem, we propose a low-cost open-source lickometer that combines a restricted infrared beam defined by optical fibers, with a poke design that allows easy access to the tongue while limiting access of other body parts and external light sources. This device also includes features for detecting nose pokes and presenting visual cues during behavioral tasks. We provide validation experiments that demonstrate the optical licko...

Decision-making is a fundamental process that guides actions by selecting between various options based on their known or presumed outcomes, often using sensory inputs (Carandini and Churchland, 2013). The neural mechanisms by which the brain integrates complex information to make decisions are typically studied by measuring neural recordings, response times, and choice accuracy using well-trained animals (Carandini and Churchland, 2013). These experiments often employ two-alternative forced-choice (2AFC) designs, where animals are trained to choose between two stimuli presented simultaneously, assuming that the animal learns the value of each stimulus and decides based on an internal comparative evaluation. However, the traditional 2AFC design may be limited, as it does not consider that stimuli are not encountered simultaneously in nature and that decision-making strategies evolve during learning (White et al., 2024). Kacelnik et al. (2011) highlight these concerns, arguing that animals’ choices on a 2A...