Synapsin III Controls Early Phases of Dopaminergic Neurons Development in Fishes and Mammals by Acting Upstream of BDNF and Cdk5 Signaling

Polymorphisms in the Synapsin III (Syn III) gene can associate with attention deficits and hyperactivity disorder (ADHD), a neurodevelopmental disorder characterized by alterations in the mesocorticolimbic and nigrostriatal dopaminergic pathways. In spite of evidence supporting that Syn III controls the development of cortical and hippocampal short-projecting neurons, whether it plays a similar role in midbrain dopaminergic neurons (mDN), owning extensively arborized long-distance multi-synaptic axonal projections, was unexplored. Our studies on mDN development in zebrafish embryos exposed to Syn III gene knock-down (KD), Syn III knock-out (ko) mice and Syn III-deleted human induced pluripotent stem cells (iPSCs)-derived neurons disclose that Syn III governs early mDN developmental stages in fishes and mammals. Differently to what observed in cortical and hippocampal neurons, this Syn III function impinges on the upstream control of brain derived neurotrophic factor (BDNF)-mediated and cAMP-dependent protein kinase 5 (Cdk5)-stimulated dendrite development. These findings have significant implications for deciphering the basis of ADHD.

High-Salt Diet Impairs the Neurons Plasticity and the Neurotransmitters-Related Biological Processes

Salt, commonly known as sodium chloride, is an important ingredient that the body requires in relatively minute quantities. However, consuming too much salt can lead to high blood pressure, heart disease and even disruption of circadian rhythms. The biological process of the circadian rhythm was first studied in Drosophila melanogaster and is well understood. Their locomotor activity gradually increases before the light is switched on and off, a phenomenon called anticipation. In a previous study, we showed that a high-salt diet (HSD) impairs morning anticipation behavior in Drosophila. Here, we found that HSD did not significantly disrupt clock gene oscillation in the heads of flies, nor did it disrupt PERIOD protein oscillation in clock neurons or peripheral tissues. Remarkably, we found that HSD impairs neuronal plasticity in the axonal projections of circadian pacemaker neurons. Interestingly, we showed that increased excitability in PDF neurons mimics HSD, which causes morning anticipation impairment. Moreover, we found that HSD significantly disrupts neurotransmitter-related biological processes in the brain. Taken together, our data show that an HSD affects the multiple functions of neurons and impairs physiological behaviors.

New perspectives on cytoskeletal dysregulation and mitochondrial mislocalization in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by selective, early degeneration of motor neurons in the brain and spinal cord. Motor neurons have long axonal projections, which rely on the integrity of neuronal cytoskeleton and mitochondria to regulate energy requirements for maintaining axonal stability, anterograde and retrograde transport, and signaling between neurons. The formation of protein aggregates which contain cytoskeletal proteins, and mitochondrial dysfunction both have devastating effects on the function of neurons and are shared pathological features across several neurodegenerative conditions, including ALS, Alzheimer's disease, Parkinson's disease, Huntington’s disease and Charcot-Marie-Tooth disease. Furthermore, it is becoming increasingly clear that cytoskeletal integrity and mitochondrial function are intricately linked. Therefore, dysregulations of the cytoskeletal network and mitochondrial homeostasis and localization, may be common pathways in the initial steps of neurodegeneration. Here we review and discuss known contributors, including variants in genetic loci and aberrant protein activities, which modify cytoskeletal integrity, axonal transport and mitochondrial localization in ALS and have overlapping features with other neurodegenerative diseases. Additionally, we explore some emerging pathways that may contribute to this disruption in ALS.

A quantitative model of sporadic axonal degeneration in the Drosophila visual system

In human neurodegenerative diseases, neurons undergo axonal degeneration months to years before they die. Here, we developed a system modelling early degenerative events in Drosophila adult photoreceptor cells. Thanks to the stereotypy of their axonal projections, this system delivers quantitative data on sporadic and progressive axonal degeneration of photoreceptor cells. Using this method, we show that exposure of adult flies to a constant light stimulation for several days overcomes the intrinsic resilience of R7 photoreceptors and leads to progressive axonal degeneration. This was not associated with apoptosis. We furthermore provide evidence that loss of synaptic integrity between R7 and a postsynaptic partner preceded axonal degeneration, thus recapitulating features of human neurodegenerative diseases. Finally, our experiments uncovered that neurotransmission to postsynaptic partners of R7 and their response are required to initiate degeneration, suggesting that postsynaptic cells signal back to the photoreceptor to maintain axonal structure. This model can be used to dissect cellular circuit mechanisms involved in the early events of axonal degeneration, allowing for a better understanding of how neurons cope with stress and lose their resilience capacities.

Impaired trigeminal control of ingestive behavior in the Prrxl1- / - mouse is associated with a lemniscal-biased orosensory deafferentation

Although peripheral deafferentation studies have demonstrated a critical role for trigeminal afference in modulating the orosensorimotor control of eating and drinking, the central trigeminal pathways mediating that control, as well as the timescale of control, remain to be elucidated. In rodents, three ascending somatosensory pathways process and relay orofacial mechanosensory input: the lemniscal, paralemniscal, and extralemniscal. Two of these pathways (the lemniscal and extralemniscal) exhibit highly structured topographic representations of the orofacial sensory surface, as exemplified by the one-to-one somatotopic mapping between vibrissae on the animals’ face and barrelettes in brainstem, barreloids in thalamus, and barrels in cortex. Here we use the Prrxl1 knockout mouse model to investigate ingestive behavior deficits associated with disruption of the lemniscal pathway. The Prrxl1 deletion disrupts somatotopic patterning and axonal projections throughout the lemniscal pathway but spares patterning in the extralemniscal nucleus. Our data reveal an imprecise and inefficient ingestive phenotype with deficits that span timescales from milliseconds to months, tightly linking trigeminal input with ingestion, from moment-to-moment consummatory to long term appetitive control. We suggest that ordered assembly of trigeminal sensory information along the lemniscal pathway is critical for the rapid and precise modulation of motor circuits driving eating and drinking action sequences.

Mapping brain-wide excitatory projectome of primate prefrontal cortex at submicron resolution: relevance to diffusion tractography

Resolving trajectories of axonal pathways in the primate prefrontal cortex remains crucial to gain insights into higher-order processes of cognition and emotion, which requires a comprehensive map of axonal projections linking demarcated subdivisions of prefrontal cortex and the rest of brain. Here we report a mesoscale excitatory projectome issued from the ventrolateral prefrontal cortex (vlPFC) to the entire macaque brain by using viral-based genetic axonal tracing in tandem with high-throughput serial two-photon tomography, which demonstrated prominent monosynaptic projections to other prefrontal areas, temporal, limbic and subcortical areas, relatively weak projections to parietal and insular cortices but no projections directly to the occipital lobe. In a common 3D space, we quantitatively validated an atlas of diffusion tractography-derived vlPFC connections with correlative enhanced green fluorescent protein-labelled axonal tracing, and observed generally good agreement except a major difference in the posterior projections of inferior fronto-occipital fasciculus. These findings raise an intriguing question as to how neural information passes along long-range association fiber bundles in macaque brains, and call for the caution of using diffusion tractography to map the wiring diagram of brain circuits.

BRAIN-DERIVED NEUROTROPHIC FACTOR IN AN ORBITOFRONTAL CORTICAL-DORSOLATERAL STRIATAL CIRCUIT GATES ALCOHOL CONSUMPTION

Brain-derived neurotrophic factor (BDNF) signaling in the dorsolateral striatum (DLS) gates alcohol self-administration in rodents. The major source of BDNF in the striatum is the cortex, and we recently found that BDNF-expressing neurons in the ventrolateral orbitofrontal cortex (vlOFC) extend axonal projections to the DLS. We therefore hypothesized that BDNF in the vlOFC to DLS circuit moderates alcohol intake. We show that overexpression of BDNF in the vlOFC, which activates BDNF signaling in the DLS, is sufficient to attenuate voluntary consumption and seeking of 20% alcohol in the home cage using a two-bottle choice paradigm. Overexpressing BDNF in the vlOFC had no effect on the consumption of a sweetened saccharin solution. In addition, BDNF overexpression in the neighboring motor cortex did not alter alcohol intake. Finally, pathway-specific overexpression of BDNF in DLS-projecting vlOFC neurons significantly reduced alcohol intake and preference. Overall, BDNF in the vlOFC, and specifically in a vlOFC-DLS pathway, keeps alcohol drinking in moderation.

An Inhibitory Medial Preoptic Circuit Mediates Innate Exploration

Animals have an innate motivation to explore objects and environments with unknown values. To this end, they need to activate neural pathways that enable exploration. Here, we reveal that photostimulation of a subset of medial preoptic area (MPA) neurons expressing the vesicular-GABA transporter gene (vgat+) and sending axonal projections to the ventrolateral periaqueductal gray (vPAG) increases exploration in a chamber but causes no place preference when tested there without photostimulation. Photoinhibition of MPAvgat–vPAG projections leads to no emotional changes as measured by normal activity in an open field assay. Electrophysiological recordings revealed that most GABAergic vPAG neurons are inhibited by MPAvgat neurons. In contrast to a previous report that suggested that MPAvgat–vPAG neurons may impart positive valence to induce place preference, our results suggest that these neurons can increase innate exploration.

Functional connectomics spanning multiple areas of mouse visual cortex

The value of an integrated approach for understanding the neocortex by combining functional characterization of single neuron activity with the underlying circuit architecture has been understood since the dawn of modern neuroscience. However, in practice, anatomical connectivity and physiology have been studied mostly separately. Following in the footsteps of previous studies that have combined physiology and anatomy in the same tissue, here we present a unique functional connectomics dataset that contains calcium imaging of an estimated 75,000 neurons from primary visual cortex (VISp) and three higher visual areas (VISrl, VISal and VISlm), that were recorded while a mouse viewed natural movies and parametric stimuli. The functional data were co-registered with electron microscopy (EM) data of the same volume which were automatically segmented, reconstructing more than 200,000 cells (neuronal and non-neuronal) and 524 million synapses. Subsequent proofreading of some neurons in this volume yielded reconstructions that include complete dendritic trees as well the local and inter-areal axonal projections. The largest proofread excitatory axon reached a length of 19 mm and formed 1,893 synapses, while the largest inhibitory axon formed 10,081 synapses. Here we release this dataset as an open access resource to the scientific community including a set of analysis tools that allows easy data access, both programmatically and through a web user interface.