Mu opioid receptor signaling in the nucleus accumbens shell increases responsiveness of satiety-modulated lateral hypothalamus neurons.

Opioid signaling in the nucleus accumbens shell (sNAcc) has been implicated in hedonic feeding and binge eating behavior. The sNAcc projects to the lateral hypothalamus (LH), and this pathway has been suggested to modulate palatability-driven feeding behavior. In this study, we investigated the effects of sNAcc mu opioid receptor (MOR) stimulation on firing rates of LH neurons in previously sated rats. Neural firing in the LH was recorded while food-deprived rats performed an operant task to obtain sweetened Intralipid (a 4% fat emulsion containing 5% sucrose) before and after bilateral sNAcc infusion of either a MOR agonist [D-Ala2, N-MePhe4, Gly-ol]-enkephalin (DAMGO) or a saline control solution. During sessions in which saline was infused into the sNAcc, the number of trials completed after infusion were significantly lower than the number completed before infusion, likely reflecting animals' increased satiety state. During sessions in which DAMGO was infused into the sNAcc, the decrease in the number of trials completed (comparing post- vs. pre-infusion trials) was significantly attenuated. Electrophysiological recording showed that the percentage of LH neurons showing an excitatory response due to behavioral events (cue presentation, lever press, lever retraction, and consumption) was reduced in post vs. pre-saline infusion period. However, the percentage of LH neurons showing excitatory responses to the same behavioral events was similar in pre- and post-DAMGO infusion periods. These findings suggest that MOR stimulation in sNAcc leads to an increase in stimulus-evoked excitatory signaling in LH neurons which could contribute to preventing satiety-induced decline in palatable food intake.

Excitation of lateral habenula neurons as a neural mechanism underlying ethanol-induced conditioned taste aversion.

KEY POINTS: The lateral habenula (LHb) has been implicated in regulation of drug-seeking behaviours through aversion-mediated learning. In this study, we recorded neuronal activity in the LHb of rats during an operant task before and after ethanol-induced conditioned taste aversion (CTA) to saccharin. Ethanol-induced CTA caused significantly higher baseline firing rates in LHb neurons, as well as elevated firing rates in response to cue presentation, lever press and saccharin taste. In a separate cohort of rats, we found that bilateral LHb lesions blocked ethanol-induced CTA. Our results strongly suggest that excitation of LHb neurons is required for ethanol-induced CTA, and point towards a mechanism through which LHb firing may regulate voluntary ethanol consumption. ABSTRACT: Ethanol, like other drugs of abuse, has both rewarding and aversive properties. Previous work suggests that sensitivity to ethanol's aversive effects negatively modulates voluntary alcohol intake and thus may be important in vulnerability to developing alcohol use disorders. We previously found that rats with lesions of the lateral habenula (LHb), which is implicated in aversion-mediated learning, show accelerated escalation of voluntary ethanol consumption. To understand neural encoding in the LHb contributing to ethanol-induced aversion, we recorded neural firing in the LHb of freely behaving, water-deprived rats before and after an ethanol-induced (1.5 g kg-1 20% ethanol, i.p.) conditioned taste aversion (CTA) to saccharin taste. Ethanol-induced CTA strongly decreased motivation for saccharin in an operant task to obtain the tastant. Comparison of LHb neural firing before and after CTA induction revealed four main differences in firing properties. First, baseline firing after CTA induction was significantly higher. Second, firing evoked by cues signalling saccharin availability shifted from a pattern of primarily inhibition before CTA to primarily excitation after CTA induction. Third, CTA induction reduced the magnitude of lever press-evoked inhibition. Finally, firing rates were significantly higher during consumption of the devalued saccharin solution after CTA induction. Next, we studied sham- and LHb-lesioned rats in our operant CTA paradigm and found that LHb lesion significantly attenuated CTA effects in the operant task. Our data demonstrate the importance of LHb excitation in regulating expression of ethanol-induced aversion and suggest a mechanism for its role in modulating escalation of voluntary ethanol intake.

Lesions of the lateral habenula increase voluntary ethanol consumption and operant self-administration, block yohimbine-induced reinstatement of ethanol seeking, and attenuate ethanol-induced conditioned taste aversion.

The lateral habenula (LHb) plays an important role in learning driven by negative outcomes. Many drugs of abuse, including ethanol, have dose-dependent aversive effects that act to limit intake of the drug. However, the role of the LHb in regulating ethanol intake is unknown. In the present study, we compared voluntary ethanol consumption and self-administration, yohimbine-induced reinstatement of ethanol seeking, and ethanol-induced conditioned taste aversion in rats with sham or LHb lesions. In rats given home cage access to 20% ethanol in an intermittent access two bottle choice paradigm, lesioned animals escalated their voluntary ethanol consumption more rapidly than sham-lesioned control animals and maintained higher stable rates of voluntary ethanol intake. Similarly, lesioned animals exhibited higher rates of responding for ethanol in operant self-administration sessions. In addition, LHb lesion blocked yohimbine-induced reinstatement of ethanol seeking after extinction. Finally, LHb lesion significantly attenuated an ethanol-induced conditioned taste aversion. Our results demonstrate an important role for the LHb in multiple facets of ethanol-directed behavior, and further suggest that the LHb may contribute to ethanol-directed behaviors by mediating learning driven by the aversive effects of the drug.

Complete reorganization of the motor cortex of adult rats following long-term spinal cord injuries.

Understanding brain reorganization following long-term spinal cord injuries is important for optimizing recoveries based on residual function as well as developing brain-controlled assistive devices. Although it has been shown that the motor cortex undergoes partial reorganization within a few weeks after peripheral and spinal cord injuries, it is not known if the motor cortex of rats is capable of large-scale reorganization after longer recovery periods. Here we determined the organization of the rat (Rattus norvegicus) motor cortex at 5 or more months after chronic lesions of the spinal cord at cervical levels using intracortical microstimulation. The results show that, in the rats with the lesions, stimulation of neurons in the de-efferented forelimb motor cortex no longer evokes movements of the forelimb. Instead, movements of the body parts in the adjacent representations, namely the whiskers and neck were evoked. In addition, at many sites, movements of the ipsilateral forelimb were observed at threshold currents. The extent of representations of the eye, jaw and tongue movements was unaltered by the lesion. Thus, large-scale reorganization of the motor cortex leads to complete filling-in of the de-efferented cortex by neighboring representations following long-term partial spinal cord injuries at cervical levels in adult rats.

Appetitive changes during salt deprivation are paralleled by widespread neuronal adaptations in nucleus accumbens, lateral hypothalamus, and central amygdala.

Salt appetite is a goal-directed behavior in which salt-deprived animals ingest high salt concentrations that they otherwise find aversive. Because forebrain areas such as the lateral hypothalamus (LH), central amygdala (CeA), and nucleus accumbens (NAc) are known to play an important role in this behavior, we recorded from these areas while water-deprived (WD) and salt-deprived (SD) rats performed a two-bottle choice test between 0.5 M salt (NaCl) and 0.4 M sucrose. In the SD state, the preference ratio for high molar salt markedly increased. Electrophysiological recordings analyzed with respect to the onset of licking clusters revealed the presence of both excitatory and inhibitory neuronal responses during salt and/or sucrose consumption. In the NAc, putative medium spiny neurons and tonically active neurons exhibited excitatory and inhibitory responses. In all areas, compared with those recorded during the WD state, neurons recorded during the SD state showed an increase in the percentage of salt-evoked excitatory responses and a decrease in the percentage of sucrose-evoked inhibitory responses, suggesting that a subset of the neuronal population in these areas codes for the increased motivational and/or hedonic value of the salt solution. In addition, in the SD state, the firing of excitatory neurons in LH and CeA became more synchronized, indicating a greater functional connectivity between salt-responsive neurons in these areas. We propose that plastic changes in the feeding-related neuronal populations of these forebrain areas arise when changes in metabolic state alter the hedonic and motivational value of a particular taste stimulus.

Reorganization of the primary motor cortex of adult macaque monkeys after sensory loss resulting from partial spinal cord injuries.

Long-term injuries to the dorsal columns of the spinal cord at cervical levels result in large-scale somatotopic reorganization of the somatosensory areas of the cortex and the ventroposterior nucleus of the thalamus. As a result of this reorganization, intact inputs from the face expand into the deafferented hand representations. Dorsal column injuries also result in permanent deficits in the use of digits for precision grip and a loss of fractionated movements of the digits. We determined whether the chronic loss of sensory inputs and the behavioral deficits caused by lesions of the dorsal columns in adult macaque monkeys affect organization of the motor cortex. The results show that, in the primary motor cortex, intracortical microstimulation evokes extension-flexion movements of the thumb at significantly fewer sites compared with the normal monkeys. There is a corresponding increase in the adduction-abduction movements. Furthermore, there is a significant increase in the thresholds of the currents required to evoke movements of the digits. Thus, long-term sensory loss in adult monkeys does not change the overall topography of the movement representation in the motor cortex but results in changes in the details of movement representations.

Large-scale expansion of the face representation in somatosensory areas of the lateral sulcus after spinal cord injuries in monkeys.

Transection of dorsal columns of the spinal cord in adult monkeys results in large-scale expansion of the face inputs into the deafferented hand region in the primary somatosensory cortex (area 3b) and the ventroposterior nucleus of thalamus. Here, we determined whether the upstream cortical areas, secondary somatosensory (S2) and parietal ventral (PV) areas, also undergo reorganization after lesions of the dorsal columns. Areas S2, PV, and 3b were mapped after long-term unilateral lesions of the dorsal columns at cervical levels in adult macaque monkeys. In areas S2 and PV, we found neurons responding to touch on the face in regions in which responses to touch on the hand and other body parts are normally seen. In the reorganized parts of S2 and PV, inputs from the chin as well as other parts of the face were observed, whereas in area 3b only the chin inputs expand into the deafferented regions. The results show that deafferentations lead to a more widespread brain reorganization than previously known. The data also show that reorganization in areas S2 and PV shares a common substrate with area 3b, but there are specific features that emerge in S2 and PV.

Overlapping representations of the neck and whiskers in the rat motor cortex revealed by mapping at different anaesthetic depths.

The primary motor cortex of mammals has an orderly representation of different body parts. Within the representation of each body part the organization is more complex, with groups of neurons representing movements of a muscle or a group of muscles. In rats, uncertainties continue to exist regarding organization of the primary motor cortex in the whisker and the neck region. Using intracortical microstimulation (ICMS) we show that movements evoked in the whisker and the neck region of the rat motor cortex are highly sensitive to the depth of anaesthesia. At light anaesthetic depth, whisker movements are readily evoked from a large medial region of the motor cortex. Lateral to this is a small region where movements of the neck are evoked. However, in animals under deep anaesthesia whisker movements cannot be evoked. Instead, neck movements are evoked from this region. The neck movement region thus becomes greatly expanded. An analysis of the threshold currents required to evoke movements at different anaesthetic depths reveals that the caudal portion of the whisker region has dual representation, of both the whisker and the neck movements. The results also underline the importance of carefully controlling the depth of anaesthesia during ICMS experiments.