Sharif A. Taha

Orexin A in the VTA Is Critical for the Induction of Synaptic Plasticity and Behavioral Sensitization to Cocaine

Dopamine neurons in the ventral tegmental area (VTA) represent a critical site of synaptic plasticity induced by addictive drugs. Orexin/hypocretin-containing neurons in the lateral hypothalamus project to the VTA, and behavioral studies have suggested that orexin neurons play an important role in motivation, feeding, and adaptive behaviors. However, the role of orexin signaling in neural plasticity is poorly understood. The present study shows that in vitro application of orexin A induces potentiation of N-methyl-D-aspartate receptor (NMDAR)-mediated neurotransmission via a PLC/PKC-dependent insertion of NMDARs in VTA dopamine neuron synapses. Furthermore, in vivo administration of an orexin 1 receptor antagonist blocks locomotor sensitization to cocaine and occludes cocaine-induced potentiation of excitatory currents in VTA dopamine neurons. These results provide in vitro and in vivo evidence for a critical role of orexin signaling in the VTA in neural plasticity relevant to addiction.

Inhibition of orexin-1/hypocretin-1 receptors inhibits yohimbine-induced reinstatement of ethanol and sucrose seeking in Long-Evans rats

RationalePrevious studies have shown that orexin-1/hypocretin-1 receptors play a role in self-administration and cue-induced reinstatement of food, drug, and ethanol seeking. In the current study, we examined the role of orexin-1/hypocretin-1 receptors in operant self-administration of ethanol and sucrose and in yohimbine-induced reinstatement of ethanol and sucrose seeking.Materials and methodsRats were trained to self-administer either 10% ethanol or 5% sucrose (30xa0min/day). The orexin-1 receptor antagonist SB334867 (0, 5, 10, 15, 20xa0mg/kg, i.p.) was administered 30xa0min before the operant self-administration sessions. After these experiments, the operant self-administration behaviors were extinguished in both the ethanol and sucrose-trained rats. Upon reaching extinction criteria, SB334867 (0, 5, 10xa0mg/kg, i.p.) was administered 30xa0min before yohimbine (0 or 2xa0mg/kg, i.p.). In a separate experiment, the effect of SB334867 (0, 15, or 20xa0mg/kg, i.p.) on general locomotor activity was determined using the open-field test.ResultsThe orexin-1 receptor antagonist, SB334867 (10, 15 and 20xa0mg/kg) decreased operant self-administration of 10% ethanol but not 5% sucrose self-administration. Furthermore, SB334867 (5 and 10xa0mg/kg) significantly decreased yohimbine-induced reinstatement of both ethanol and sucrose seeking. SB334867 did not significantly affect locomotor activity measured using the open-field test.ConclusionsThe results suggest that inhibition of OX-1/Hcrt-1 receptors modulates operant ethanol self-administration and also plays a significant role in yohimbine-induced reinstatement of both ethanol and sucrose seeking in rats.

Encoding of Palatability and Appetitive Behaviors by Distinct Neuronal Populations in the Nucleus Accumbens

Obesity is a major public health problem. Palatability (i.e., the reinforcing value of food, derived from orosensory cues) is a significant factor in determining food intake and contributes to increased consumption leading to obesity. The nucleus accumbens is a ventral striatal region that is important for both appetitive and consummatory behaviors and has been implicated in modulating palatability. In this study, we investigated palatability encoding in the firing of nucleus accumbens neurons in rats. Nucleus accumbens neurons with significant changes in firing rate during consummatory behavior displayed one of two principal firing patterns. Firing in one class of nucleus accumbens neurons was correlated with the palatability of sucrose reinforcers; changes in neural activity in this class consisted primarily of excitations. Within this group of neurons, a subset was sensitive to the relative value of sucrose reinforcers, as assessed by a behavioral contrast paradigm. A second and distinct population of nucleus accumbens neurons, with changes in firing that were pre-dominantly inhibitions, was not sensitive to reinforcer palatability; rather, these inhibitions were present even during unreinforced bouts of licking. In addition, the onset of these inhibitions typically occurred before the initiation of the licking behavior itself. We propose that two primary classes of nucleus accumbens neurons contribute to neural processing immediately before and during reinforcer consumption: inhibitions related to initiation and maintenance of consummatory behaviors and excitations that encode reinforcer palatability.

Inhibitions of Nucleus Accumbens Neurons Encode a Gating Signal for Reward-Directed Behavior

The nucleus accumbens (NAcc) is critical in the control of goal-directed behavior. Pharmacological studies suggest that the NAcc may act in both instructive and permissive modes; however, previous electrophysiological studies in behaving rats have reported firing patterns consistent with an instructive, but not permissive, role for NAcc neurons. We now report that a subset of NAcc neurons shows a long-lasting inhibition in firing rate whose onset precedes initiation of goal-directed sequences of behavior and terminates at the conclusion of the sequence. Together with data from previous behavioral studies, this firing pattern suggests that, when active, these neurons tonically inhibit appetitive and consummatory behaviors and that, when inhibited, these neurons permissively gate those behaviors.

Autophosphorylation of αCaMKII Is Required for Ocular Dominance Plasticity

Abstract Experience is a powerful sculptor of developing neural connections. In the primary visual cortex (V1), cortical connections are particularly susceptible to the effects of sensory manipulation during a postnatal critical period. At the molecular level, this activity-dependent plasticity requires the transformation of synaptic depolarization into changes in synaptic weight. The molecule α calcium-calmodulin kinase type II (αCaMKII) is known to play a central role in this transformation. Importantly, αCaMKII function is modulated by autophosphorylation, which promotes Ca 2+ -independent kinase activity. Here we show that mice possessing a mutant form of αCaMKII that is unable to autophosphorylate show impairments in ocular dominance plasticity. These results confirm the importance of αCaMKII in visual cortical plasticity and suggest that synaptic changes induced by monocular deprivation are stored specifically in glutamatergic synapses made onto excitatory neurons.

A Pause in Nucleus Accumbens Neuron Firing Is Required to Initiate and Maintain Feeding

Nucleus accumbens (NAc) inactivation increases food intake, indicating that NAc neurons exert ongoing inhibition of feeding. We previously described a subpopulation of NAc neurons that pause during sucrose licking and proposed that the pause permits consumption. We tested this hypothesis by first recording NAc neurons during sucrose consumption, and then electrically stimulating through the same electrodes. A large proportion of NAc shell and core neurons were inhibited during sucrose consumption, and local electrical stimulation abruptly interrupted licking. Effective stimulation sites were more anterior than ineffective sites in NAc. At low stimulus intensities, licking resumed immediately on stimulation offset. The latency to lick resumption from NAc neuron inhibition onset (∼460 ms) was very similar to that after electrical stimulation offset (∼440 ms). These results directly support the hypothesis that a significant subpopulation of NAc neurons inhibit palatable food consumption and that a pause in their firing is required to initiate and maintain consumption.

Nucleus accumbens dopamine release is necessary and sufficient to promote the behavioral response to reward-predictive cues

The nucleus accumbens is part of the neural circuit that controls reward-seeking in response to reward-predictive cues. Dopamine release in the accumbens is essential for the normal functioning of this circuit. Previous studies have shown that injection of dopamine receptor antagonists into the accumbens severely impairs an animals ability to perform operant behaviors specified by predictive cues. Furthermore, excitations and inhibitions of accumbens neurons evoked by such cues are abolished by inactivation of the ventral tegmental area, the major dopaminergic input to the accumbens. These results indicate that dopamine is necessary to elicit neural activity in the accumbens that drives the behavioral response to cues. Here we show that accumbens dopamine release is causal to the rats reward-seeking behavioral response by demonstrating that dopamine in this structure is both necessary and sufficient to promote the appropriate behavioral response to reward-predictive cues.

Rapid ocular dominance plasticity requires cortical but not geniculate protein synthesis.

Synaptic plasticity is a multistep process in which rapid, early phases eventually give way to slower, more enduring stages. Diverse forms of synaptic change share a common requirement for protein synthesis in the late stages of plasticity, which are often associated with structural rearrangements. Ocular dominance plasticity in the primary visual cortex (V1) is a long-lasting form of activity-dependent plasticity comprised of well-defined physiological and anatomical stages. The molecular events underlying these stages remain poorly understood. Using the protein synthesis inhibitor cycloheximide, we investigated a role for protein synthesis in ocular dominance plasticity. Suppression of cortical, but not geniculate, protein synthesis impaired rapid ocular dominance plasticity, while leaving neuronal responsiveness intact. These findings suggest that structural changes underlying ocular dominance plasticity occur rapidly following monocular occlusion, and cortical changes guide subsequent alterations in thalamocortical afferents.

Cue‐evoked encoding of movement planning and execution in the rat nucleus accumbens

The nucleus accumbens is involved in the modulation of motivated behaviour by reward‐associated sensory information. However, little is known about the specific nature of the nucleus accumbens contribution to generating movement. We investigated motor encoding by nucleus accumbens neurons in rats performing a delayed response task that allowed us to dissociate the effects of sensory and motor events on firing. In a subset of neurons, firing in the delay period preceding movement was highly selective; this selectivity was tightly correlated with the direction of the subsequent movement, but not with the sensory properties of the instructive cue. Direction selectivity in this population of neurons developed over the course of the delay period, with the strongest selectivity apparent just prior to movement onset. Selectivity was also apparent in nucleus accumbens neurons during movement, such that firing showed a tight correlation with movement direction, but not the instructive cue presented nor the spatial destination of the movement. These results are consistent with the hypothesis that a subpopulation of nucleus accumbens neurons contributes to the selection and execution of specific motivated behaviours.

Endogenous opioids encode relative taste preference

Endogenous opioid signaling contributes to the neural control of food intake. Opioid signaling is thought to regulate palatability, the reward value of a food item as determined by orosensory cues such as taste and texture. The reward value of a food reflects not only these sensory properties but also the relative value of competing food choices. In the present experiment, we used a consummatory contrast paradigm to manipulate the relative value of a sucrose solution for two groups of rats. Systemic injection of the nonspecific opioid antagonist naltrexone suppressed sucrose intake; for both groups, however, this suppression was selective, occurring only for the relatively more valuable sucrose solution. Our results indicate that endogenous opioid signaling contributes to the encoding of relative reward value.