The lamprey belongs to the phylogenetically oldest group of vertebrates that diverged from the mammalian evolutionary line 560 million years ago. A comparison between the lamprey and mammalian basal ganglia establishes a detailed similarity regarding its input from cortex/pallium and thalamus, as well as its intrinsic organisation and projections of the output nuclei. This means that the basal ganglia circuits now present in rodents and primates most likely had evolved already at the dawn of vertebrate evolution. This includes the 'direct pathway' with striatal projection neurons (SPNs) expressing dopamine D1 receptors, which act to inhibit the tonically active GABAergic output neurons in globus pallidus interna and substantia nigra pars reticulata that at rest keep the brainstem motor centres under tonic inhibition. The 'indirect pathway' with dopamine D2 receptor-expressing SPNs and intrinsic basal ganglia nuclei is also conserved. The net effect of the direct pathway is to disinhibit brainstem motor centres and release motor programs, while the indirect pathway instead will suppress motor activity. Transmitters, connectivity and membrane properties are virtually identical in lamprey and rodent basal ganglia. We predict that the basal ganglia contains a series of modules each controlling a given pattern of behaviour including locomotion, eye-movements, posture, and chewing that contain both the direct pathway to release a motor program and the indirect pathway to inhibit competing behaviours. The phasic dopamine input serves value-based decisions and motor learning. During vertebrate evolution with a progressively more diverse motor behaviour, the number of modules will have increased progressively. These new modules with a similar design will be used to control newly developed patterns of behaviour - a process referred to as exaptation.

Neurons interact in networks distributed throughout the brain. While much effort has focused on whole-brain calcium imaging, advances in genetically encoded voltage indicators raise the question of whether it might be possible to image neuronal voltage across entire brains. Achieving this requires a microscope with high volumetric imaging rates and signal-to-noise ratio. Here we present a remote-scanning light-sheet microscope capable of imaging genetically encoded voltage indicator-expressing neurons distributed throughout much of the brain of larval zebrafish at a volumetric rate of 200.8 Hz. We measured voltage traces from approximately one-quarter of all brain neurons. We found that neurons firing at different times during a sequence occupied different locations: visually evoked sequences mapped across the optic tectum, whereas stimulus-independent bursts were mapped across the cerebellum and medulla. Imaging voltage of neurons distributed in many brain regions may open new frontiers for understanding fundamental neural system operations.

Glucagon-like peptide 1 receptor agonists (GLP1RAs) effectively reduce body weight and improve metabolic outcomes; however, established peptide-based therapies require injections and are complex to manufacture. Small-molecule GLP1RAs promise oral bioavailability and scalable manufacturing, but their selective binding to human versus rodent receptors has limited mechanistic studies. Here we developed humanized GLP1R mouse models to investigate how small-molecule GLP1RAs influence feeding behaviour. We found that these compounds regulate both homeostatic and hedonic feeding through parallel neural circuits. Beyond engaging canonical hypothalamic and hindbrain networks that control metabolic homeostasis, GLP1RAs recruit a discrete population of Glp1r-expressing neurons in the central amygdala, which selectively suppress the consumption of palatable foods by reducing dopamine release in the nucleus accumbens. Stimulating these central amygdalar neurons curtails hedonic feeding, whereas targeted deletion of the receptor in this cell population specifically diminishes the anorectic efficacy of GLP1RAs for reward-driven intake. These findings identify a neural circuit through which small-molecule GLP1RAs modulate reward processing, with implications for the treatment of substance-use disorder and binge eating.

Recent advances in the field of Voltage Imaging, with a special focus on new constructs and novel implementations.

Basal Ganglia Advances is a collection highlighting research on the structure, function, and disorders of the basal ganglia. It features studies spanning neuroscience, clinical insights, and computational models, serving as a hub for advances in movement, cognition, and behavior.

Work related to place tuning, spatial navigation, orientation and direction. Mainly includes articles on connectivity in the hippocampus, retrosplenial cortex, and related areas.

Neurons interact in networks distributed throughout the brain. While much effort has focused on whole-brain calcium imaging, advances in genetically encoded voltage indicators raise the question of whether it might be possible to image neuronal voltage across entire brains. Achieving this requires a microscope with high volumetric imaging rates and signal-to-noise ratio. Here we present a remote-scanning light-sheet microscope capable of imaging genetically encoded voltage indicator-expressing neurons distributed throughout much of the brain of larval zebrafish at a volumetric rate of 200.8 Hz. We measured voltage traces from approximately one-quarter of all brain neurons. We found that neurons firing at different times during a sequence occupied different locations: visually evoked sequences mapped across the optic tectum, whereas stimulus-independent bursts were mapped across the cerebellum and medulla. Imaging voltage of neurons distributed in many brain regions may open new frontiers for understanding fundamental neural system operations.

The integration of synaptic inputs is a fundamental function of neurons. In the traditional model, excitatory inputs are summed at the soma to generate action potentials. However, how synaptic inputs are integrated by dendrites in vivo remains poorly explored. We used intravital two-photon dendritic imaging with a genetically encoded voltage indicator (accelerated sensor of action potentials 5) together with somatic whole-cell patch clamp recordings to investigate how synaptic depolarizations are transferred to the soma in pyramidal neurons of the mouse somatosensory cortex. We studied the integration of synaptic inputs under spontaneous and sensory-evoked conditions, as well as following electrical and optogenetic stimulation. In all cases, while multiple inputs evoked measurable depolarizations in the cell body, isolated synaptic potentials were strongly attenuated. Our results suggest that isolated synaptic inputs have a minimal contribution to somatic depolarization, whereas coincident inputs within short temporal windows are more effective, indicating a regime of dendritic integration that favors coincident or clustered neuronal activity in cortical networks.

Immunosenescence is not a uniform decline but a trajectory shaped jointly by age and sex. Using continuous high-dimensional immunophenotyping, we show that aging T cells accumulate a senescent signature of CD28 loss and CD57 gain, and that males reach an inverted CD4:CD8 ratio earlier and more severely than females. We argue that age-by-sex stratification should guide vaccination and geroprotective strategies in an aging population.