Appetite suppression occurs following a meal and also during conditions when it is unfavorable to eat, such as during illness or exposure to toxins. A brain region hypothesized to play a role in appetite suppression is the parabrachial nucleus (PBN)1-3, a heterogeneous population of neurons surrounding the superior cerebellar peduncle in the brainstem. The PBN is thought to mediate the suppression of appetite induced by the anorectic hormones amylin and cholecystokinin, as well as lithium chloride and lipopolysaccharide, compounds that mimic the effects of toxic foods and bacterial infections, respectively4-6. Hyperactivity of the PBN is also thought to cause starvation following ablation of orexigenic agouti-related peptide (AgRP) neurons in adult mice1,7. However, the identities of PBN neurons that regulate feeding are unknown, as are the functionally relevant downstream projections. Here we identify calcitonin gene-related peptide (CGRP)-expressing neurons in the outer external lateral subdivision of the PBN that project to the laterocapsular division of the central nucleus of the amygdala (CeAlc) as forming a functionally important circuit for the suppression of appetite. Using genetically-encoded anatomical, optogenetic8, and pharmacogenetic9 tools, we demonstrate that activation of PBelo CGRP neurons projecting to the CeAlc suppresses appetite. In contrast, inhibition of these neurons increases food intake in circumstances when mice do not normally eat and prevents starvation in adult AgRP neuron-ablated mice. Taken together, our data demonstrate that this neural circuit from the PBN to CeAlc mediates appetite suppression in conditions when it is unfavorable to eat. This neural circuit may provide targets for therapeutic intervention to overcome or promote appetite.

Midbrain dopamine (DA) neurons fire in 2 characteristic modes, tonic and phasic, which are thought to modulate distinct aspects of behavior. However, the inability to selectively disrupt these patterns of activity has hampered the precise definition of the function of these modes of signaling. Here, we addressed the role of phasic DA in learning and other DA-dependent behaviors by attenuating DA neuron burst firing and subsequent DA release, without altering tonic neural activity. Disruption of phasic DA was achieved by selective genetic inactivation of NMDA-type, ionotropic glutamate receptors in DA neurons. Disruption of phasic DA neuron activity impaired the acquisition of numerous conditioned behavioral responses, and dramatically attenuated learning about cues that predicted rewarding and aversive events while leaving many other DA-dependent behaviors unaffected.cue-dependent learning ͉ mouse behavior ͉ electrophysiology ͉ cyclic voltammetry D opamine (DA) neurons of the ventral midbrain project to the dorsal and ventral striatum, as well as to other corticolimbic structures such as the hippocampus, amygdala, and prefrontal cortex. Differential DA release (tonic or phasic) is thought to activate distinct signal transduction cascades through the activation of postsynaptic inhibitory and excitatory G protein coupled receptors. Phasic DA is proposed to activate excitatory, low-affinity DA D1-like receptors (Rs) (1, 2) to facilitate long-term potentiation of excitatory synaptic transmission and enhance activity of the basal ganglia direct pathway facilitating appropriate action selection during goal-directed behavior. Conversely, tonic DA release is proposed to act on inhibitory, high-affinity DA D2Rs to facilitate long-term depression of cortico-striatal synapses and suppress activity of medium spiny neurons (MSNs) of the basal ganglia indirect pathway (1, 3-5). Thus, coordinate D1R and D2R activation modulates motor and cognitive function, and facilitates behavioral flexibility by a dichotomous control of striatal plasticity (5).During reinforcement learning shifts in phasic DA neuron responses from primary rewards, to reward predicting, stimuli are thought to reflect the acquisition of incentive salience for the predictive conditioned stimuli (6-10). Coincident DA and glutamate release onto MSNs during conditioned-stimulus response learning facilitates long-term potentiation of excitatory synapses that is thought to underlie reinforcement learning (1, 2, 11). Pharmacological or genetic disruption of D1R signaling impairs learning in numerous behavioral paradigms (2, 11); thus, phasic DA acting through D1R is thought to facilitate memory acquisition by ''stamping-in'' stimulus-response associations.Although considerable correlative electrophysiological evidence, as well as pharmacological and genetic evidence, supports an important role of phasic DA in stamping-in cue-reward associations, other evidence suggests that DA is not necessary for learning conditioned-stimulus responses. Mice genetically modified to...

The hippocampus is traditionally thought to transmit contextual information to limbic structures where it acquires valence. Using freely moving calcium imaging and optogenetics, we show that while the dorsal CA1 subregion of the hippocampus is enriched in place cells, ventral CA1 (vCA1) is enriched in anxiety cells that are activated by anxiogenic environments and required for avoidance behavior. Imaging cells defined by their projection target revealed that anxiety cells were enriched in the vCA1 population projecting to the lateral hypothalamic area (LHA) but not to the basal amygdala (BA). Consistent with this selectivity, optogenetic activation of vCA1 terminals in LHA but not BA increased anxiety and avoidance, while activation of terminals in BA but not LHA impaired contextual fear memory. Thus, the hippocampus encodes not only neutral but also valence-related contextual information, and the vCA1-LHA pathway is a direct route by which the hippocampus can rapidly influence innate anxiety behavior.

SUMMARY Animals learn to avoid harmful situations by associating a neutral stimulus with a painful one, resulting in a stable threat memory. In mammals, this form of learning requires the amygdala. Although pain is the main driver of aversive learning, the mechanism that transmits pain signals to the amygdala is not well resolved. Here we show that neurons expressing calcitonin gene-related peptide (CGRP) in the parabrachial nucleus are critical for relaying pain signals to the central nucleus of amygdala, and that this pathway may transduce the affective motivational aspects of pain. Genetic silencing of CGRP neurons blocks pain responses and memory formation, while their optogenetic stimulation produces defensive responses and a threat memory. The pain-recipient neurons in the central amygdala expressing CGRP receptors are also critical for establishing a threat memory. The identification of the neural circuit conveying affective pain signals may be pertinent for treating pain conditions with psychiatric comorbidities.

A fundamental question in developmental biology is how a limited number of growth factors and their cognate receptors coordinate the formation of tissues and organs endowed with enormous morphological complexity. We report that the related neurotrophins NGF and NT-3, acting through a common receptor, TrkA, are required for sequential stages of sympathetic axon growth and, thus, innervation of target fields. Yet, while NGF supports TrkA internalization and retrograde signaling from distal axons to cell bodies to promote neuronal survival, NT-3 cannot. Interestingly, final target-derived NGF promotes expression of the p75 neurotrophin receptor, in turn causing a reduction in the sensitivity of axons to intermediate target-derived NT-3. We propose that a hierarchical neurotrophin signaling cascade coordinates sequential stages of sympathetic axon growth, innervation of targets, and survival in a manner dependent on the differential control of TrkA internalization, trafficking, and retrograde axonal signaling.

Neuronal connections are established and refined through a series of developmental programs that involve axon and dendrite specification, process growth, target innervation, cell death and synaptogenesis. Many of these developmental events are regulated by target-derived neurotrophins and their receptors, which signal retrogradely over long distances from distal-most axons to neuronal cell bodies. Recent work has established many of the cellular and molecular events that underlie retrograde signalling and the importance of these events for both development and maintenance of proper neural connectivity.

SummaryParenting is essential for the survival and wellbeing of mammalian offspring but we lack a circuit-level understanding of how distinct components of this behaviour are orchestrated. Here we investigate how Galanin-expressing neurons in the medial preoptic area (MPOAGal) coordinate motor, motivational, hormonal and social aspects of parenting. These neurons integrate inputs from a large number of brain areas, whose activation depends on the animal’s sex and reproductive state. Subsets of MPOAGal neurons form discrete pools defined by their projection sites. While the MPOAGal population is active during all episodes of parental behaviour, individual pools are tuned to characteristic aspects of parenting. Optogenetic manipulation of MPOAGal projections mirrors this specificity, affecting discrete parenting components. This functional organization, reminiscent of the control of motor sequences by pools of spinal cord neurons, provides a new model for how discrete elements of a social behaviour are generated at the circuit level.

Summary A single exposure to drugs of abuse produces an NMDA receptor (NMDAR)-dependent long-term potentiation (LTP) of AMPA receptor (AMPAR) currents in DA neurons; however, the importance of LTP for various aspects of drug addiction is unclear. To test the role of NMDAR-dependent plasticity in addictive behavior, we genetically inactivated functional NMDAR signaling exclusively in DA neurons (KO mice). Inactivation of NMDARs results in increased AMPAR-mediated transmission that is indistinguishable from the increases associated with a single cocaine exposure, yet locomotor responses to multiple drugs of abuse were unaltered in the KO mice. The initial phase of locomotor sensitization to cocaine is intact; however, the delayed sensitization that occurs with prolonged cocaine withdrawal did not occur. Conditioned behavioral responses for cocaine-testing environment were also absent in the KO mice. These findings provide evidence for a role of NMDAR signaling in DA neurons for specific behavioral modifications associated with drug seeking behaviors.