Internal-state-dependent control of feeding behavior via hippocampal ghrelin signaling.

Hunger is an internal state that not only invigorates feeding but also acts as a contextual cue for higher-order control of anticipatory feeding-related behavior. The ventral hippocampus is crucial for differentiating optimal behavior across contexts, but how internal contexts such as hunger influence hippocampal circuitry is unknown. In this study, we investigated the role of the ventral hippocampus during feeding behavior across different states of hunger in mice. We found that activity of a unique subpopulation of neurons that project to the nucleus accumbens (vS-NAc neurons) increased when animals investigated food, and this activity inhibited the transition to begin eating. Increases in the level of the peripheral hunger hormone ghrelin reduced vS-NAc activity during this anticipatory phase of feeding via ghrelin-receptor-dependent increases in postsynaptic inhibition and promoted the initiation of eating. Together, these experiments define a ghrelin-sensitive hippocampal circuit that informs the decision to eat based on internal state.

Nucleus accumbens dopamine release reflects Bayesian inference during instrumental learning.

Dopamine release in the nucleus accumbens has been hypothesized to signal reward prediction error, the difference between observed and predicted reward, suggesting a biological implementation for reinforcement learning. Rigorous tests of this hypothesis require assumptions about how the brain maps sensory signals to reward predictions, yet this mapping is still poorly understood. In particular, the mapping is non-trivial when sensory signals provide ambiguous information about the hidden state of the environment. Previous work using classical conditioning tasks has suggested that reward predictions are generated conditional on probabilistic beliefs about the hidden state, such that dopamine implicitly reflects these beliefs. Here we test this hypothesis in the context of an instrumental task (a two-armed bandit), where the hidden state switches repeatedly. We measured choice behavior and recorded dLight signals reflecting dopamine release in the nucleus accumbens core. Model comparison based on the behavioral data favored models that used Bayesian updating of probabilistic beliefs. These same models also quantitatively matched the dopamine measurements better than non-Bayesian alternatives. We conclude that probabilistic belief computation plays a fundamental role in instrumental performance and associated mesolimbic dopamine signaling.

Two opposing hippocampus to prefrontal cortex pathways for the control of approach and avoidance behaviour.

The decision to either approach or avoid a potentially threatening environment is thought to rely upon the coordinated activity of heterogeneous neural populations in the hippocampus and prefrontal cortex (PFC). However, how this circuitry is organized to flexibly promote both approach or avoidance at different times has remained elusive. Here, we show that the hippocampal projection to PFC is composed of two parallel circuits located in the superficial or deep pyramidal layers of the CA1/subiculum border. These circuits have unique upstream and downstream connectivity, and are differentially active during approach and avoidance behaviour. The superficial population is preferentially connected to widespread PFC inhibitory interneurons, and its activation promotes exploration; while the deep circuit is connected to PFC pyramidal neurons and fast spiking interneurons, and its activation promotes avoidance. Together this provides a mechanism for regulation of behaviour during approach avoidance conflict: through two specialized, parallel circuits that allow bidirectional hippocampal control of PFC.

Control of parallel hippocampal output pathways by amygdalar long-range inhibition.

Projections from the basal amygdala (BA) to the ventral hippocampus (vH) are proposed to provide information about the rewarding or threatening nature of learned associations to support appropriate goal-directed and anxiety-like behaviour. Such behaviour occurs via the differential activity of multiple, parallel populations of pyramidal neurons in vH that project to distinct downstream targets, but the nature of BA input and how it connects with these populations is unclear. Using channelrhodopsin-2-assisted circuit mapping in mice, we show that BA input to vH consists of both excitatory and inhibitory projections. Excitatory input specifically targets BA- and nucleus accumbens-projecting vH neurons and avoids prefrontal cortex-projecting vH neurons, while inhibitory input preferentially targets BA-projecting neurons. Through this specific connectivity, BA inhibitory projections gate place-value associations by controlling the activity of nucleus accumbens-projecting vH neurons. Our results define a parallel excitatory and inhibitory projection from BA to vH that can support goal-directed behaviour.

Biased Connectivity of Brain-wide Inputs to Ventral Subiculum Output Neurons.

The ventral subiculum (vS) of the mouse hippocampus coordinates diverse behaviors through heterogeneous populations of pyramidal neurons that project to multiple distinct downstream regions. Each of these populations of neurons is proposed to integrate a unique combination of thousands of local and long-range synaptic inputs, but the extent to which this occurs remains unknown. To address this, we employ monosynaptic rabies tracing to study the input-output relationship of vS neurons. Analysis of brain-wide inputs reveals quantitative input differences that could be explained by a combination of both the identity of the downstream target and the spatial location of the postsynaptic neurons within vS. These results support a model of combined topographical and output-defined connectivity of vS inputs. Overall, we reveal prominent heterogeneity in brain-wide inputs to the vS parallel output circuitry, providing a basis for the selective control of individual projections during behavior.

Loss of Dendritic Complexity Precedes Neurodegeneration in a Mouse Model with Disrupted Mitochondrial Distribution in Mature Dendrites.

Correct mitochondrial distribution is critical for satisfying local energy demands and calcium buffering requirements and supporting key cellular processes. The mitochondrially targeted proteins Miro1 and Miro2 are important components of the mitochondrial transport machinery, but their specific roles in neuronal development, maintenance, and survival remain poorly understood. Using mouse knockout strategies, we demonstrate that Miro1, as opposed to Miro2, is the primary regulator of mitochondrial transport in both axons and dendrites. Miro1 deletion leads to depletion of mitochondria from distal dendrites but not axons, accompanied by a marked reduction in dendritic complexity. Disrupting postnatal mitochondrial distribution in vivo by deleting Miro1 in mature neurons causes a progressive loss of distal dendrites and compromises neuronal survival. Thus, the local availability of mitochondrial mass is critical for generating and sustaining dendritic arbors, and disruption of mitochondrial distribution in mature neurons is associated with neurodegeneration.

Cocaine exposure reorganizes cell type- and input-specific connectivity in the nucleus accumbens.

Repeated exposure to cocaine alters the structural and functional properties of medium spiny neurons (MSNs) in the nucleus accumbens (NAc). These changes suggest a rewiring of the NAc circuit, with an enhancement of excitatory synaptic connections onto MSNs. However, it is unknown how drug exposure alters the balance of long-range afferents onto different cell types in the NAc. Here we used whole-cell recordings, two-photon microscopy, optogenetics and pharmacogenetics to show how repeated cocaine exposure alters connectivity in the mouse NAc medial shell. Cocaine selectively enhanced amygdala innervation of MSNs expressing D1 dopamine receptors (D1-MSNs) relative to D2-MSNs. We also found that amygdala activity was required for cocaine-induced changes to behavior and connectivity. Finally, we established how heightened amygdala innervation can explain the structural and functional changes evoked by cocaine. Our findings reveal how exposure to drugs of abuse fundamentally reorganizes cell type- and input-specific connectivity in the NAc.

Exaggerated translation causes synaptic and behavioural aberrations associated with autism.

Autism spectrum disorders (ASDs) are an early onset, heterogeneous group of heritable neuropsychiatric disorders with symptoms that include deficits in social interaction skills, impaired communication abilities, and ritualistic-like repetitive behaviours. One of the hypotheses for a common molecular mechanism underlying ASDs is altered translational control resulting in exaggerated protein synthesis. Genetic variants in chromosome 4q, which contains the EIF4E locus, have been described in patients with autism. Importantly, a rare single nucleotide polymorphism has been identified in autism that is associated with increased promoter activity in the EIF4E gene. Here we show that genetically increasing the levels of eukaryotic translation initiation factor 4E (eIF4E) in mice results in exaggerated cap-dependent translation and aberrant behaviours reminiscent of autism, including repetitive and perseverative behaviours and social interaction deficits. Moreover, these autistic-like behaviours are accompanied by synaptic pathophysiology in the medial prefrontal cortex, striatum and hippocampus. The autistic-like behaviours displayed by the eIF4E-transgenic mice are corrected by intracerebroventricular infusions of the cap-dependent translation inhibitor 4EGI-1. Our findings demonstrate a causal relationship between exaggerated cap-dependent translation, synaptic dysfunction and aberrant behaviours associated with autism.

Subcellular connectivity underlies pathway-specific signaling in the nucleus accumbens.

We found that medium spiny neurons (MSNs) in both the direct and indirect pathways of the mouse nucleus accumbens (NAc) receive inputs from the cortex, thalamus and hippocampus. However, hippocampal inputs were much weaker onto indirect MSNs, where they contacted small spines located in the distal dendrites. This selective targeting means that these inputs must be gated by subthreshold depolarization to trigger action potentials and influence NAc output.

Mitochondrial trafficking and the provision of energy and calcium buffering at excitatory synapses.

Neuronal postsynaptic currents consume most of the brain's energy supply. Delineating how neurons control the distribution, morphology and function of the energy-producing mitochondria that fuel synaptic communication is therefore important for our understanding of nervous system function and pathology. Here we review recent insights into the molecular mechanisms that control activity-dependent regulation of mitochondrial trafficking, morphology and activity at excitatory synapses. We also consider some implications of this regulation for synaptic function and plasticity and discuss how this may contribute to synaptic dysfunction and signalling in neurological disease, with a focus on Alzheimer's disease.

NMDA receptors regulate GABAA receptor lateral mobility and clustering at inhibitory synapses through serine 327 on the γ2 subunit.

Modification of the number of GABA(A) receptors (GABA(A)Rs) clustered at inhibitory synapses can regulate inhibitory synapse strength with important implications for information processing and nervous system plasticity and pathology. Currently, however, the mechanisms that regulate the number of GABA(A)Rs at synapses remain poorly understood. By imaging superecliptic pHluorin tagged GABA(A)R subunits we show that synaptic GABA(A)R clusters are normally stable, but that increased neuronal activity upon glutamate receptor (GluR) activation results in their rapid and reversible dispersal. This dispersal correlates with increases in the mobility of single GABA(A)Rs within the clusters as determined using single-particle tracking of GABA(A)Rs labeled with quantum dots. GluR-dependent dispersal of GABA(A)R clusters requires Ca(2+) influx via NMDA receptors (NMDARs) and activation of the phosphatase calcineurin. Moreover, the dispersal of GABA(A)R clusters and increased mobility of individual GABA(A)Rs are dependent on serine 327 within the intracellular loop of the GABA(A)R γ2 subunit. Thus, NMDAR signaling, via calcineurin and a key GABA(A)R phosphorylation site, controls the stability of synaptic GABA(A)Rs, with important implications for activity-dependent control of synaptic inhibition and neuronal plasticity.

Delivery of GABAARs to synapses is mediated by HAP1-KIF5 and disrupted by mutant huntingtin.

The density of GABA(A) receptors (GABA(A)Rs) at synapses regulates brain excitability, and altered inhibition may contribute to Huntington's disease, which is caused by a polyglutamine repeat in the protein huntingtin. However, the machinery that delivers GABA(A)Rs to synapses is unknown. We demonstrate that GABA(A)Rs are trafficked to synapses by the kinesin family motor protein 5 (KIF5). We identify the adaptor linking the receptors to KIF5 as the huntingtin-associated protein 1 (HAP1). Disrupting the HAP1-KIF5 complex decreases synaptic GABA(A)R number and reduces the amplitude of inhibitory postsynaptic currents. When huntingtin is mutated, as in Huntington's disease, GABA(A)R transport and inhibitory synaptic currents are reduced. Thus, HAP1-KIF5-dependent GABA(A)R trafficking is a fundamental mechanism controlling the strength of synaptic inhibition in the brain. Its disruption by mutant huntingtin may explain some of the defects in brain information processing occurring in Huntington's disease and provides a molecular target for therapeutic approaches.

Control of mitochondrial transport and localization in neurons.

Mitochondria play an essential role in ATP generation, calcium buffering and apoptotic signalling. In neurons, the transport of mitochondria to specific locations where they are needed has emerged as an important process for correct nerve cell function. Recent studies have shed light on the mechanisms that control mitochondrial transport and localization in neurons. We describe the machinery that is important for constitutive transport of mitochondria throughout the cell, and highlight recent advances in our understanding of how signalling pathways can converge on this machinery and allow for rapid activity-dependent control of mitochondrial trafficking and localization. Regulation of mitochondrial trafficking might work in concert with mitochondrial tethering systems to give precise control of mitochondrial delivery and localization to regions of high energy and calcium buffering requirements within neurons.

Miro1 is a calcium sensor for glutamate receptor-dependent localization of mitochondria at synapses.

Energy use, mainly to reverse ion movements in neurons, is a fundamental constraint on brain information processing. Trafficking of mitochondria to locations in neurons where there are large ion fluxes is essential for powering neural function. Mitochondrial trafficking is regulated by Ca2+ entry through ionotropic glutamate receptors, but the underlying mechanism is unknown. We show that the protein Miro1 links mitochondria to KIF5 motor proteins, allowing mitochondria to move along microtubules. This linkage is inhibited by micromolar levels of Ca2+ binding to Miro1. With the EF hand domains of Miro1 mutated to prevent Ca2+ binding, Miro1 could still facilitate mitochondrial motility, but mitochondrial stopping induced by glutamate or neuronal activity was blocked. Activating neuronal NMDA receptors with exogenous or synaptically released glutamate led to Miro1 positioning mitochondria at the postsynaptic side of synapses. Thus, Miro1 is a key determinant of how energy supply is matched to energy usage in neurons.

GTPase dependent recruitment of Grif-1 by Miro1 regulates mitochondrial trafficking in hippocampal neurons.

The transport of mitochondria to specific neuronal locations is critical to meet local cellular energy demands and for buffering intracellular calcium. A critical role for kinesin motor proteins in mitochondrial transport in neurons has been demonstrated. Currently however the molecular mechanisms that underlie the recruitment of motor proteins to mitochondria, and how this recruitment is regulated remain unclear. Here we show that a protein trafficking complex comprising the adaptor protein Grif-1 and the atypical GTPase Miro1 can be detected in mammalian brain where it is localised to neuronal mitochondria. Increasing Miro1 expression levels recruits Grif-1 to mitochondria. This results in an enhanced transport of mitochondria towards the distal ends of neuronal processes. Uncoupling Grif-1 recruitment to mitochondria by expressing a Grif-1/Miro1 binding fragment dramatically reduces mitochondrial transport into neuronal processes. Altering Miro1 function by mutating its first GTPase domain affects Miro's ability to recruit Grif-1 to mitochondria and in addition alters mitochondrial distribution and shape along neuronal processes. These data suggest that Miro1 and the kinesin adaptor Grif-1 play an important role in regulating mitochondrial transport in neurons.