Metaplasticity in the Ventral Pallidum as a Potential Marker for the Propensity to Gain Weight in Chronic High-Calorie Diet.

A major driver of obesity is the increasing palatability of processed foods. Although reward circuits promote the consumption of palatable food, their involvement in obesity remains unclear. The ventral pallidum (VP) is a key hub in the reward system that encodes the hedonic aspects of palatable food consumption and participates in various proposed feeding circuits. However, there is still no evidence for its involvement in developing diet-induced obesity. Here we examine, using male C57BL6/J mice and patch-clamp electrophysiology, how chronic high-fat high-sugar (HFHS) diet changes the physiology of the VP and whether mice that gain the most weight differ in their VP physiology from others. We found that 10-12 weeks of HFHS diet hyperpolarized and decreased the firing rate of VP neurons without a major change in synaptic inhibitory input. Within the HFHS group, the top 33% weight gainers (WGs) had a more hyperpolarized VP with longer latency to fire action potentials on depolarization compared with bottom 33% of weight gainers (i.e., non-weight gainers). WGs also showed synaptic potentiation of inhibitory inputs both at the millisecond and minute ranges. Moreover, we found that the tendency to potentiate the inhibitory inputs to the VP might exist in overeating mice even before exposure to HFHS, thus making it a potential property of being an overeater. These data point to the VP as a critical player in obesity and suggest that hyperpolarized membrane potential of, and potentiated inhibitory inputs to, VP neurons may play a significant role in promoting the overeating of palatable food.SIGNIFICANCE STATEMENT In modern world, where highly palatable food is readily available, overeating is often driven by motivational, rather than metabolic, needs. It is thus conceivable that reward circuits differ between obese and normal-weight individuals. But is such difference, if it exists, innate or does it develop with overeating? Here we reveal synaptic properties in the ventral pallidum, a central hub of reward circuits, that differ between mice that gain the most and the least weight when given unlimited access to highly palatable food. We show that these synaptic differences also exist without exposure to palatable food, potentially making them innate properties that render some more susceptible than others to overeat. Thus, the propensity to overeat may have a strong innate component embedded in reward circuits.

Cocaine Dysregulates Dynorphin Modulation of Inhibitory Neurotransmission in the Ventral Pallidum in a Cell-Type-Specific Manner.

Cocaine-driven changes in the modulation of neurotransmission by neuromodulators are poorly understood. The ventral pallidum (VP) is a key structure in the reward system, in which GABA neurotransmission is regulated by opioid neuropeptides, including dynorphin. However, it is not known whether dynorphin acts differently on different cell types in the VP and whether its effects are altered by withdrawal from cocaine. Here, we trained wild-type, D1-Cre, A2A-Cre, or vGluT2-Cre:Ai9 male and female mice in a cocaine conditioned place preference protocol followed by 2 weeks of abstinence, and then recorded GABAergic synaptic input evoked either electrically or optogenetically onto identified VP neurons before and after applying dynorphin. We found that after cocaine CPP and abstinence dynorphin attenuated inhibitory input to VPGABA neurons through a postsynaptic mechanism. This effect was absent in saline mice. Furthermore, this effect was seen specifically on the inputs from nucleus accumbens medium spiny neurons expressing either the D1 or the D2 dopamine receptor. Unlike its effect on VPGABA neurons, dynorphin surprisingly potentiated the inhibitory input on VPvGluT2 neurons, but this effect was abolished after cocaine CPP and abstinence. Thus, dynorphin has contrasting influences on GABA input to VPGABA and VPvGluT2 neurons and these influences are affected differentially by cocaine CPP and abstinence. Collectively, our data suggest a role for dynorphin in withdrawal through its actions in the VP. As VPGABA and VPvGluT2 neurons have contrasting effects on drug-seeking behavior, our data may indicate a complex role for dynorphin in withdrawal from cocaine.SIGNIFICANCE STATEMENT The ventral pallidum consists mainly of GABAergic reward-promoting neurons, but it also encloses a subgroup of aversion-promoting glutamatergic neurons. Dynorphin, an opioid neuropeptide abundant in the ventral pallidum, shows differential modulation of GABA input to GABAergic and glutamatergic pallidal neurons and may therefore affect both the rewarding and aversive aspects of withdrawal. Indeed, abstinence after repeated exposure to cocaine alters dynorphin actions in a cell-type-specific manner; after abstinence dynorphin suppresses the inhibitory drive on the "rewarding" GABAergic neurons but ceases to modulate the inhibitory drive on the "aversive" glutamatergic neurons. This reflects a complex role for dynorphin in cocaine reward and abstinence.

Projection-Specific Potentiation of Ventral Pallidal Glutamatergic Outputs after Abstinence from Cocaine.

The ventral pallidum (VP) is a central node in the reward system that is strongly implicated in reward and addiction. Although the majority of VP neurons are GABAergic and encode reward, recent studies revealed a novel glutamatergic neuronal population in the VP [VP neurons expressing the vesicular glutamate transporter 2 (VPVGluT2)], whose activation generates aversion. Withdrawal from drugs has been shown to induce drastic synaptic changes in neuronal populations associated with reward, such as the ventral tegmental area (VTA) or nucleus accumbens neurons, but less is known about cocaine-induced synaptic changes in neurons classically linked with aversion. Here, we demonstrate that VPVGluT2 neurons contact different targets with different intensities, and that cocaine conditioned place preference (CPP) training followed by abstinence selectively potentiates their synapses on targets that encode aversion. Using whole-cell patch-clamp recordings combined with optogenetics in male and female transgenic mice, we show that VPVGluT2 neurons preferentially contact aversion-related neurons, such as lateral habenula neurons and VTA GABAergic neurons, with minor input to reward-related neurons, such as VTA dopamine and VP GABA neurons. Moreover, after cocaine CPP and abstinence, the VPVGluT2 input to the aversion-related structures is potentiated, whereas the input to the reward-related structures is depressed. Thus, cocaine CPP followed by abstinence may allow VPVGluT2 neurons to recruit aversion-related targets more readily and therefore be part of the mechanism underlying the aversive symptoms seen after withdrawal.SIGNIFICANCE STATEMENT The biggest problem in drug addiction is the high propensity to relapse. One central driver for relapse events is the negative aversive symptoms experienced by addicts during withdrawal. In this work, we propose a possible mechanism for the intensification of aversive feelings after withdrawal that involves the glutamatergic neurons of the ventral pallidum. We show not only that these neurons are most strongly connected to aversive targets, such as the lateral habenula, but also that, after abstinence, their synapses on aversive targets are strengthened, whereas the synapses on other rewarding targets are weakened. These data illustrate how after abstinence from cocaine, aversive pathways change in a manner that may contribute to relapse.

Chronic calorie-dense diet drives differences in motivated food seeking between obesity-prone and resistant mice.

Obesity results from overconsumption of energy, partly because of the inability to refrain from highly palatable rewarding foods. Even though palatable food is available to everyone, only a fraction of the population develops obesity. We previously showed that following chronic exposure to highly palatable food animals that gained the most weight also showed addictive-like motivation to seek for palatable food. An important question remains-is this extreme, addictive-like, motivation to consume palatable food the cause or the consequence of diet-induced obesity? Here, we show that obesity-prone (OP) mice exhibit higher motivation for palatable food consumption compared with obesity-resistant mice even before developing obesity, but that the full manifestation of this high motivation to eat is expressed only after chronic exposure to high-fat-high-sugar (HFHS) diet. HFHS diet also impairs performance in the operant food-seeking task selectively in OP mice, an impairment that persists even after 2 weeks of abstinence from HFHS food. Overall, our data suggest that while some aspects of food motivation are high in OP mice already before developing obesity, the chronic exposure to HFHS food accentuates it and drives the development of obesity.

Tracking inflammation in the epileptic rat brain by bi-functional fluorescent and magnetic nanoparticles.

Correct localization of epileptic foci can improve surgical outcome in patients with drug-resistant seizures. Our aim was to demonstrate that systemically injected nanoparticles identify activated immune cells, which have been reported to accumulate in epileptogenic brain tissue. Fluorescent and magnetite-labeled nanoparticles were injected intravenously to rats with lithium-pilocarpine-induced chronic epilepsy. Cerebral uptake was studied ex vivo by confocal microscopy and MRI. Cellular uptake and biological effects were characterized in vitro in murine monocytes and microglia cell lines. Microscopy confirmed that the nanoparticles selectively accumulate within myeloid cells in the hippocampus, in association with inflammation. The nanoparticle signal was also detectable by MRI. The in vitro studies demonstrate rapid nanoparticle uptake and good cellular tolerability. We show that nanoparticles can target myeloid cells in epileptogenic brain tissue. This system can contribute to pre-surgical and intra-surgical localization of epileptic foci, and assist in detecting immune system involvement in epilepsy.

Engaging high-school students in scientific conferences.

Scientific meetings rarely involve the local community and have minimal educational and scientific impacts on it. Here, we report the successful engagement of high-school students in scientific conferences. To promote science education and trust in science, we call upon conference attendees and organizers to involve high-school students in their meetings.

The role of the nucleus accumbens and ventral pallidum in feeding and obesity.

Obesity is a growing global epidemic that stems from the increasing availability of highly-palatable foods and the consequent enhanced calorie consumption. Extensive research has shown that brain regions that are central to reward seeking modulate feeding and evidence linking obesity to pathology in such regions have recently started to accumulate. In this review we focus on the contribution of two major interconnected structures central to reward processing, the nucleus accumbens and the ventral pallidum, to obesity. We first review the known literature linking these structures to feeding behavior, then discuss recent advances connecting pathology in the nucleus accumbens and ventral pallidum to obesity, and finally examine the similarities and differences between drug addiction and obesity in the context of these two structures. The understanding of how pathology in brain regions involved in reward seeking and consumption may drive obesity and how mechanistically similar obesity and addiction are, is only now starting to be revealed. We hope that future research will advance knowledge in the field and open new avenues to studying and treating obesity.

Emergence of novel representations in primary motor cortex and premotor neurons during associative learning.

Neurons in the motor areas of cortex play a key role in associating sensory instructions with movements. However, their ability to acquire and maintain representations of novel stimulus features, especially when these features are behaviorally relevant, remains unknown. We investigated neuronal changes in these areas during and after associative learning, by training monkeys on a novel reaching task that required associating target colors with movement directions. Before and after learning, the monkeys performed a well known center-out task. We found that during learning, up to 48% of the neurons developed learning-related responses, differentiating between the associative task and the center-out task, although movement kinematics were the same. After learning, on returning to the center-out task in which color was irrelevant, many of these neurons maintained their response to the associative task; they displayed novel sensitivity to the color of the target that was relevant during learning. These neuronal responses prevailed in both the primary motor cortex and the ventral and dorsal premotor cortices, without degrading the information that the neurons firing carried about movement direction. Our results show that motor cortical neurons can rapidly develop and maintain sensitivities to novel arbitrary sensory features such as color, when such features are behaviorally relevant.

Folate homeostasis in epileptic rats.

Folate is involved in metabolic processes and it has been implicated in both aggravation and amelioration of seizures. The aim of the current work was to study the effect of chronic temporal lobe epilepsy (TLE) on the plasma and brain concentrations of folate and on its uptake carriers in the brain - the reduced folate carrier (RFC), folate receptor α (FRα) and proton coupled folate transporter (PCFT). We utilized the rat lithium pilocarpine model for TLE. Approximately two months following status epilepticus, rats with spontaneous recurrent seizures (SRS) were sacrificed for brain and plasma folate concentration analyses and folate uptake carrier expression studies. RT-PCR and western blot analyses were utilized for quantification of folate carriers' mRNAs and proteins, respectively. The distribution of folate carriers in the brain was studied using immunohistochemistry. In the SRS rats we found lower plasma concentrations (10 ±â€¯0.9 in control vs. 6.6 ±â€¯1.6 ng/ml in SRS, P < 0.05), but preserved cortical and increased hippocampal levels of folate (0.5 ±â€¯0.1 in control vs. 0.9 ±â€¯0.2 ng/mg in SRS, P = 0.055). Hippocampus - to - plasma ratio of folate concentration was 3-fold higher in the SRS group, compared with the controls (0.13 ±â€¯0.03 vs. 0.04 ±â€¯0.02, respectively; P < 0.01). mRNA and protein levels of the folate uptake carriers did not differ between SRS rats and controls. However, immunofluorescent staining quantification revealed that the emission intensity of both RFC and FRα was elevated 8-fold and 4-fold, respectively, in hippocampal CA1 neurons of SRS rats, compared to controls (P < 0.01). PCFT was unquantifiable. If corroborated by complementary research in humans, the findings of this study may be utilized clinically for supplemental therapy planning, in imaging the epileptic focus, and for drug delivery into the epileptic brain. Further studies are required for better elucidating the clinical and mechanistic significance of altered folate balances in the epileptic brain.

Single neurons in M1 and premotor cortex directly reflect behavioral interference.

Some motor tasks, if learned together, interfere with each other's consolidation and subsequent retention, whereas other tasks do not. Interfering tasks are said to employ the same internal model whereas noninterfering tasks use different models. The division of function among internal models, as well as their possible neural substrates, are not well understood. To investigate these questions, we compared responses of single cells in the primary motor cortex and premotor cortex of primates to interfering and noninterfering tasks. The interfering tasks were visuomotor rotation followed by opposing visuomotor rotation. The noninterfering tasks were visuomotor rotation followed by an arbitrary association task. Learning two noninterfering tasks led to the simultaneous formation of neural activity typical of both tasks, at the level of single neurons. In contrast, and in accordance with behavioral results, after learning two interfering tasks, only the second task was successfully reflected in motor cortical single cell activity. These results support the hypothesis that the representational capacity of motor cortical cells is the basis of behavioral interference and division between internal models.

Segregation between acquisition and long-term memory in sensorimotor learning.

It is widely accepted that learning first involves generating new memories and then consolidating them into long-term memory. Thus learning is generally viewed as a single continuous process with two sequential stages; acquisition and consolidation. Here, we tested an alternative hypothesis proposing that acquisition and consolidation take place, at least partly, in parallel. Human subjects learned two visuomotor tasks. One task required moving a cursor under visuomotor rotation and the other required arbitrary association of colour to direction of movement. Subjects learned the two tasks in sequence, and were tested for acquisition of the second immediately after learning the first, and for retention of the first on the following day. The results show that learning one task led to proactive interference to acquisition of the second. However, this interference was not accompanied by retroactive interference to consolidation of the first task, indicating that acquisition and consolidation can be uncoupled.