The primate striatum is composed of limbic, cognitive, and sensorimotor functional domains. Although the effects of cocaine have generally been associated with the ventral striatum, or limbic domain, recent evidence in rodents suggests the involvement of the dorsal striatum (cognitive and sensorimotor domains) in cocaine self-administration. The goals of the present studies were to map the topography of the functional response to cocaine throughout the entire extent of the striatum of monkeys self-administering cocaine and determine whether this response is modified by chronic exposure to cocaine. Rhesus monkeys were trained to self-administer 0.3 mg/kg per injection cocaine for 5 d (initial stages; n ϭ 4) or 100 d (chronic stages; n ϭ 4) and compared with monkeys trained to respond under an identical schedule of food reinforcement (n ϭ 6). Monkeys received 30 reinforcers per session, and metabolic mapping was conducted at the end of the 5th or 100th self-administration session. In the initial phases of cocaine exposure, self-administration significantly decreased functional activity in the ventral striatum, but only in very restricted portions of the dorsal striatum. With chronic cocaine self-administration, however, the effects of cocaine intensified and spread dorsally to include most aspects of both caudate and putamen. Early experiences with cocaine, then, involve mainly the limbic domain, an area that mediates motivational and affective functions. In contrast, as exposure to cocaine continues, the impact of cocaine impinges progressively on the processing of sensorimotor and cognitive information, as well as the affective and motivational information processed in the ventral striatum.

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The nucleus of the solitary tract (NTS) is a key gateway for meal-related signals entering the brain from the periphery. However, the chemical mediators crucial to this process have not been fully elucidated. We reveal that a subset of NTS neurons containing cholecystokinin (CCKNTS) is responsive to nutritional state and that their activation reduces appetite and body weight in mice. Cell-specific anterograde tracing revealed that CCKNTS neurons provide a distinctive innervation of the paraventricular nucleus of the hypothalamus (PVH), with fibers and varicosities in close apposition to a subset of melanocortin-4 receptor (MC4RPVH) cells, which are also responsive to CCK. Optogenetic activation of CCKNTS axon terminals within the PVH reveal the satiating function of CCKNTS neurons to be mediated by a CCKNTS→PVH pathway that also encodes positive valence. These data identify the functional significance of CCKNTS neurons and reveal a sufficient and discrete NTS to hypothalamus circuit controlling appetite.DOI: http://dx.doi.org/10.7554/eLife.12225.001

Balance in the body's hormonal axes depends on feedback onto neuroendocrine hypothalamic neurons. This phenomenon involves transcriptional and biosynthetic effects, yet less is known about the potential rapid modulation of electrical properties. Here, we investigated this issue in the lactotrophic axis, in which the pituitary hormone prolactin is tonically inhibited by tuberoinfundibular dopamine (TIDA) neurons located in the hypothalamic arcuate nucleus. Whole-cell recordings were performed on slices of the rat hypothalamus. In the presence of prolactin, spontaneously oscillating TIDA cells depolarized, switched from phasic to tonic discharge, and exhibited broadened action potentials. The underlying prolactin-induced current is composed of separate low-and high-voltage components that include the activation of a transient receptor potential-like current and the inhibition of a Ca 2ϩ -dependent BK-type K ϩ current, respectively, as revealed by ion substitution experiments and pharmacological manipulation. The two components of the prolactin-induced current appear to be mediated through distinct signaling pathways as the high-voltage component is abolished by the phosphoinositide 3-kinase blocker wortmannin, whereas the low-voltage component is not. This first description of the central electrophysiological actions of prolactin suggests a novel feedback mechanism. By simultaneously enhancing the discharge and spike duration of TIDA cells, increased serum prolactin can promote dopamine release to limit its own secretion with implications for the control of lactation, sexual libido, fertility, and body weight.

The pituitary hormone, prolactin, triggers lactation in nursing mothers. Under nonlactating conditions, prolactin secretion is suppressed by powerful inhibition from hypothalamic tuberoinfundibular dopamine (TIDA) neurons. Although firing pattern has been suggested as integral to neuroendocrine control, the electrical behavior of TIDA cells remains unknown. We demonstrate that rat TIDA neurons discharge rhythmically in a robust 0.05 Hz oscillation. The oscillation is phase locked between neurons, and while it persists during chemical synaptic transmission blockade, it is abolished by gap junction antagonists. Thyrotropin-releasing hormone (TRH) potently stimulates prolactin release, an effect assumed to take place in the pituitary. In TIDA cells, TRH caused a transition from phasic to tonic firing through combined pre- and postsynaptic effects. These findings suggest a model for prolactin regulation where a TIDA network switch from oscillations to sustained discharge converts dopamine from an antagonist at high concentrations to a functional agonist as dopamine output from the network decreases.