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SummaryNeural activity is increasingly recognized as a critical regulator of cancer growth. In the brain, neuronal activity robustly influences glioma growth both through paracrine mechanisms and through electrochemical integration of malignant cells into neural circuitry via neuron-to-glioma synapses, while perisynaptic neurotransmitter signaling drives breast cancer brain metastasis growth. Outside of the CNS, innervation of tumors such as prostate, breast, pancreatic and gastrointestinal cancers by peripheral nerves similarly regulates cancer progression. However, the extent to which the nervous system regulates lung cancer progression, either in the lung or when metastatic to brain, is largely unexplored. Small cell lung cancer (SCLC) is a lethal high-grade neuroendocrine tumor that exhibits a strong propensity to metastasize to the brain. Here we demonstrate that, similar to glioma, metastatic SCLC cells in the brain co-opt neuronal activity-regulated mechanisms to stimulate growth and progression. Optogenetic stimulation of cortical neuronal activity drives proliferation and invasion of SCLC brain metastases. In the brain, SCLC cells exhibit electrical currents and consequent calcium transients in response to neuronal activity, and direct SCLC cell membrane depolarization is sufficient to promote the growth of SCLC tumors. In the lung, vagus nerve transection markedly inhibits primary lung tumor formation, progression and metastasis, highlighting a critical role for innervation in overall SCLC initiation and progression. Taken together, these studies illustrate that neuronal activity plays a crucial role in dictating SCLC pathogenesis in both primary and metastatic sites.

Within the basal ganglia, striatal dopamine (DA) and acetylcholine (Ach) are essential for the selection and reinforcement of motor actions and decision making. In vitro studies have revealed a circuit local to the striatum by which each of these two neurotransmitters directly regulates release of the other. Ach, released by a unique population of cholinergic interneurons (CINs), drives DA release via direct axonal depolarization. In turn, DA inhibits CIN activity via dopamine D2 receptors (D2R). Whether and how this circuit contributes to striatal function in vivo remains unknown. To define the in vivo role of this circuit, we monitored Ach and DA signals in the ventrolateral striatum of mice performing a reward-based decision-making task. We establish that DA and Ach exhibit multiphasic and anticorrelated transients that are modulated by decision history and reward outcome. However, CIN perturbations reveal that DA dynamics and reward-prediction error encoding do not require Ach release by CINs. On the other hand, CIN-specific deletion of D2Rs shows that DA inhibits Ach levels in a D2R-dependent manner, and loss of this regulation impairs decision-making. To determine how other inputs to striatum shape Ach signals, we assessed the contribution of projections from cortex and thalamus and found that glutamate release from both sources is required for Ach release. Altogether, we uncover a dynamic relationship between DA and Ach during decision making and reveal modes of CIN regulation by local DA signals and long-range cortical and thalamic inputs. These findings deepen our understanding of the neurochemical basis of decision making and behavior.

Nutrient availability varies seasonally and spatially in the wild. The resulting nutrient limitation or restricted access to nutrients pose a major challenge for every organism. While many animals, such as hibernating animals, evolved strategies to overcome periods of nutrient scarcity, the cellular mechanisms of these strategies are poorly understood. Cave environments represent an extreme example of nutrient deprived environments since the lack of sunlight and therefore primary energy production drastically diminishes the nutrient availability. Here, we used Astyanax mexicanus, which includes river-dwelling surface fish and cave adapted cavefish populations to study the genetic adaptation to nutrient limitations. We show that cavefish populations store large amounts of fat in different body regions when fed ad libitum in the lab. We found higher expression of lipogenesis genes in cavefish livers when fed the same amount of food as surface fish, suggesting an improved ability of cavefish to use lipogenesis to convert available energy into triglycerides for storage into adipose tissue. Moreover, the lipid metabolism regulator, Peroxisome proliferator-activated receptor γ (Pparγ), is upregulated at both transcript and protein levels in cavefish livers. Chromatin Immunoprecipitation sequencing (ChIP seq) showed that Pparγ binds cavefish promoter regions of genes to a higher extent than surface fish. Finally, we identified two possible regulatory mechanisms of Pparγ in cavefish: higher amounts of ligands of the nuclear receptor, and nonsense mutations in per2, a known repressor of Pparγ. Taken together, our study reveals that upregulated Pparγ promotes higher levels of lipogenesis in the liver and contributes to higher body fat accumulation in cavefish populations, an important adaptation to nutrient limited environments.

SUMMARYNeuron-glia relationships play a critical role in the regulation of synapse formation and neuronal specification. The cellular and molecular mechanisms by which neurons and astrocytes communicate and coordinate are not well understood. Here we demonstrate that the canonical Sonic hedgehog (Shh) pathway is active in cortical astrocytes, where it acts to coordinate layer-specific synaptic connectivity and functional circuit development. We show that Ptch1 is a Shh receptor that is expressed by cortical astrocytes during development and that Shh signaling is necessary and sufficient to promote the expression of layer-specific astrocyte genes involved in regulating synapse formation and function. Loss of Shh in layer V neurons reduces astrocyte complexity and coverage by astrocytic processes in tripartite synapses, moreover, cell-autonomous activation of Shh signaling in astrocytes promotes cortical excitatory synapse formation. Together, these results suggest that Shh secreted from deep layer cortical neurons acts to specialize the molecular and functional features of astrocytes during development to shape circuit assembly and function.

The cerebral cortex contains neurons that express choline acetyltransferase (ChAT) and are a potential local source of acetylcholine. However, the neurotransmitters released by cortical ChAT+ neurons and their synaptic connectivity are unknown. We show that the nearly all cortical ChAT+ neurons are specialized VIP+ interneurons that release GABA strongly onto other inhibitory interneurons and acetylcholine sparsely onto layer 1 interneurons and other VIP+/ChAT+ interneurons. This differential transmission of ACh and GABA based on the postsynaptic target neuron is reflected in VIP+/ChAT+ interneuron pre-synaptic terminals, as quantitative molecular analysis shows that only a subset of these are specialized to release acetylcholine. In addition, we identify a separate, sparse population of non-VIP ChAT+ neurons in the medial prefrontal cortex with a distinct developmental origin that robustly release acetylcholine in layer 1. These results demonstrate both cortex-region heterogeneity in cortical ChAT+ interneurons and target-specific co-release of acetylcholine and GABA.

SUMMARYThe mammalian cortex is populated by neurons derived from neural progenitors located throughout the embryonic telencephalon. Excitatory neurons are derived from progenitors located in the dorsal telencephalon, while inhibitory interneurons are generated by ventral telencephalic progenitors. The transcriptional regulator PRDM16 is expressed by radial glia, neural progenitors present in both regions; however, its mechanisms of action are still not fully understood. It is unclear if PRDM16 functions plays a role in neurogenesis in both dorsal and ventral progenitor lineages, and if so, whether it does so by regulating common or unique networks of genes. Here, we show thatPrdm16expression in MGE progenitors is required for maintaining their proliferative capacity and for the production of proper numbers of pallial GABAergic interneurons. PRDM16 binds to cis-regulatory elements and represses the expression of region-specific neuronal differentiation genes, thereby controlling the timing of neuronal maturation. Our results highlight the importance of PRDM16 for the development of both excitatory and inhibitory cortical circuits. We demonstrate the existence of convergent developmental gene expression programs regulated by PRDM16, which utilize both common and region-specific sets of genes in the cortex and the MGE to control the proliferative capacity of neural progenitors, ensuring the generation of correct numbers of cortical neurons.

During mitosis, the genome is transformed from a decondensed, transcriptionally active state to a highly condensed, transcriptionally inactive state. Mitotic chromosome reorganization is marked by the general attenuation of transcription on chromosome arms, yet how the cell regulates nuclear and chromatin-associated RNAs after chromosome condensation and nuclear envelope breakdown is unknown. SAF-A/hnRNPU is an abundant nuclear protein with RNA-to-DNA tethering activity, coordinated by two spatially distinct nucleic acid binding domains. Here we show that RNA is evicted from prophase chromosomes through Aurora-B-dependent phosphorylation of the SAF-A DNA-binding domain; failure to execute this pathway leads to accumulation of SAF-A:RNA complexes on mitotic chromosomes and elevated rates of anaphase segregation defects. This work reveals a role for Aurora-B in removing chromatin-associated RNAs during prophase, and demonstrates that Aurora-B dependent relocalization of SAF-A during cell division contributes to the fidelity of chromosome segregation.

The controlled and volitional release of urine, or micturition, serves a fundamental physiological function and, in many species, is critical for social communication. In mice, the decision to release urine is modulated by external and internal factors such as environmental stimuli and social history and is transmitted to the spinal cord via the pontine micturition center (PMC). The neural pathways by which social experience and sensory stimuli interact to control PMC activity and regulate micturition are unclear. Here we establish a behavioral paradigm in which mice, depending on their strain, social experience, and immediate sensory context, display either high or low territory-covering micturition (TCM). We demonstrate that social context is represented by coordinated global activity changes in the urination network upstream of the PMC, whereas sensory context is represented by the activation of discrete nodes in the network. Furthermore, we show that the lateral hypothalamic area (LHA), which is directly upstream of PMC, is a key node that can switch micturition behavior between high and low TCM modes.

The modulation of cortex by acetylcholine (ACh) is typically thought to originate from long-range projections arising in the basal forebrain. However, a subset of VIP interneurons express ChAT, the synthetic enzyme for ACh, and are a potential local source of cortical ACh. Which neurotransmitters these VIP/ChAT interneurons (VCINs) release is unclear, and which post-synaptic cell types these transmitters target is not known. Using quantitative molecular analysis of VCIN pre-synaptic terminals, we show expression of the molecular machinery to release both ACh and GABA, with ACh release restricted to a subset of boutons. A systematic survey of potential post-synaptic cell types shows that VCINs release GABA primarily onto other inhibitory interneuron subtypes, while ACh neurotransmission is notably sparse, with most ACh release onto layer 1 interneurons and other VCINs. Therefore, VCINs are an alternative source of cortical ACh signaling that supplement GABA-mediated disinhibition with highly targeted excitation through ACh.