Medial Ventral Striatum Research Articles

A comparison of how deep brain stimulation in two targets with anti-compulsive efficacy modulates brain activity using fMRI in awake rats.

Deep brain stimulation (DBS) is an established neuromodulatory intervention against otherwise treatment-refractory obsessive-compulsive disorder (OCD). Several DBS targets, all of which are part of brain networks connecting basal ganglia and prefrontal cortex, alleviate OCD symptoms. Stimulation of these targets is thought to unfold its therapeutic effect by modulation of network activity through internal capsule (IC) connections. Research into DBS-induced network changes and the nature of IC-related effects of DBS in OCD is needed to further improve DBS. Here, we studied the effects of DBS at the ventral medial striatum (VMS) and IC on blood-oxygen level dependent (BOLD) responses in awake rats using functional magnetic resonance imaging (fMRI). BOLD-signal intensity was measured in five regions of interest (ROIs): medial and orbital prefrontal cortex, nucleus accumbens (NAc), IC area, and mediodorsal thalamus. In previous rodent studies, stimulation at both target locations resulted in a reduction of OCD-like behavior and activation of prefrontal cortical areas. Therefore, we hypothesized that stimulation at both targets would result in partially overlapping BOLD responses. Both differential and overlapping activity between VMS and IC stimulation was found. Stimulating the caudal part of the IC resulted in activation around the electrode, while stimulating the rostral part of the IC resulted in increased cross-correlations between the IC area, orbitofrontal cortex, and NAc. Stimulation of the dorsal part of the VMS resulted in increased activity in the IC area, suggesting this area is activated during both VMS and IC stimulation. This activation is also indicative of VMS-DBS impacting corticofugal fibers running through the medial caudate into the anterior IC, and both VMS and IC DBS might act on these fibers to induce OCD-reducing effects. These results show that rodent fMRI with simultaneous electrode stimulation is a promising approach to study the neural mechanisms of DBS. Comparing the effects of DBS in different target areas has the potential to improve our understanding of the neuromodulatory changes that take place across various networks and connections in the brain. Performing this research in animal disease models will lead to translational insights in the mechanisms underlying DBS, and can aid improvement and optimization of DBS in patient populations.

Enhanced H3K4 Trimethylation in TNF-α Promoter Gene Locus with Cell Apoptosis in the Ventral-Medial Striatum following Opioid Withdrawal of Neonatal Rat Offspring from Morphine-Addicted Mothers.

Prenatal opioid exposure might disturb epigenetic programming in the brain of neonatal offspring with various consequences for gene expressions and behaviors. This study determined whether altered trimethylation of histone 3 at lysine 4 (H3K4me3) in the promoter of the tumor necrosis factor-α (tnf-α) gene with neural cell apoptosis was involved in the ventral-medial striatum, an important brain region for withdrawal symptoms, of neonatal rat offspring from morphine-addicted mothers. Female adult rats were injected with morphine before gestation and until 14 days after giving birth. On postnatal day 14 (P14), rat offspring from morphine-addicted mothers were subjected to an opioid-withdrawal protocol and were analyzed 2 or 8 h after administration of that protocol. Expressions of the TNF-α protein, H3K4me3 in the tnf-α promoter gene, and neural cell apoptosis within the ventral-medial striatum of neonatal rat offspring were evaluated. In the absence of significant opioid withdrawal (2 h after initiation of the opioid-withdrawal protocol on P14), prenatal morphine exposure led to increased levels of H3K4me3 in the tnf-α promoter gene, of the TNF-α protein, and of neural cell apoptosis within the ventral-medial striatum of neonatal rat offspring. Following opioid withdrawal (8 h after initiation of the opioid-withdrawal protocol on P14), differential expression of H3K4me3 in the tnf-α promoter gene locus and upregulation of the level of TNF-α protein expression were further enhanced in these offspring. In addition, increased levels of caspase-3 and neural cell apoptosis were also observed. Taken together, this study revealed that prenatal opioid exposure can activate an epigenetic histone mechanism which regulates proinflammatory factor generation, which hence, led to cell apoptotic damage within the ventral-medial striatum of neonatal rat offspring from morphine-addicted mothers. More importantly, the opioid-withdrawal episode may provide augmented effects for the abovementioned alterations and could lead to deleterious effects in the neonatal brain of such offspring.

Acute Stress Enhances Associative Learning via Dopamine Signaling in the Ventral Lateral Striatum.

Acute stress transiently increases vigilance, enhancing the detection of salient stimuli in one's environment. This increased perceptual sensitivity is thought to promote the association of rewarding outcomes with relevant cues. The mesolimbic dopamine system is critical for learning cue-reward associations. Dopamine levels in the ventral striatum are elevated following exposure to stress. Together, this suggests that the mesolimbic dopamine system could mediate the influence of acute stress on cue-reward learning. To address this possibility, we examined how a single stressful experience influenced learning in an appetitive pavlovian conditioning task. Male rats underwent an episode of restraint prior to the first conditioning session. This acute stress treatment augmented conditioned responding in subsequent sessions. Voltammetry recordings of mesolimbic dopamine levels demonstrated that acute stress selectively increased reward-evoked dopamine release in the ventral lateral striatum (VLS), but not in the ventral medial striatum. Antagonizing dopamine receptors in the VLS blocked the stress-induced enhancement of conditioned responding. Collectively, these findings illustrate that stress engages dopamine signaling in the VLS to facilitate appetitive learning.SIGNIFICANCE STATEMENT Acute stress influences learning about aversive and rewarding outcomes. Dopamine neurons are sensitive to stress and critical for reward learning. However, it is unclear whether stress regulates reward learning via dopamine signaling. Using fast-scan cyclic voltammetry as rats underwent pavlovian conditioning, we demonstrate that a single stressful experience increases reward-evoked dopamine release in the ventral lateral striatum. This enhanced dopamine signal accompanies a long-lasting increase in conditioned behavioral responding. These findings highlight that the ventral lateral striatum is a node for mediating the effect of stress on reward processing.

Pattern of dopamine signaling during aversive events predicts active avoidance learning

Learning to avoid aversive outcomes is an adaptive strategy to limit one's future exposure to stressful events. However, there is considerable variance in active avoidance learning across a population. The mesolimbic dopamine system contributes to behaviors elicited by aversive stimuli, although it is unclear if the heterogeneity in active avoidance learning is explained by differences in dopamine transmission. Furthermore, it is not known how dopamine signals evolve throughout active avoidance learning. To address these questions, we performed voltammetry recordings of dopamine release in the ventral medial striatum throughout training on inescapable footshock and signaled active avoidance tasks. This approach revealed differences in the pattern of dopamine signaling during the aversive cue and the safety period that corresponded to subsequent task performance. Dopamine transmission throughout the footshock bout did not predict performance but rather was modulated by the prior stress exposure. Additionally, we demonstrate that dopamine encodes a safety prediction error signal, which illustrates that ventral medial striatal dopamine release conveys a learning signal during both appetitive and aversive conditions.

Operant Costs Modulate Dopamine Release to Self-Administered Cocaine.

The costs associated with obtaining illicit drugs can fluctuate depending upon the relative drug availability. As a consequence of the changing costs, the effort that one must exert to obtain drugs is dynamic. Considerable evidence illustrates a critical role for dopamine in the ventral medial striatum in mediating drug reinforcement. However, little is known regarding how dopamine release is affected by changes in the costs associated with earning drugs. We used fast-scan cyclic voltammetry to determine how changes in the operant requirement affected dopamine release to self-administered cocaine in male rats. Dopamine release to cocaine infusions increased across trials during self-administration sessions using a fixed-ratio reinforcement schedule with a low operant requirement. However, increasing the operant requirement abolished the within-session elevation in dopamine release to drug rewards. This effect was not due to underlying changes in preinfusion dopamine levels and was not explained by cocaine levels in the brain. This within-session increase in dopamine release to cocaine infusions reemerged when the operant requirement was lowered. Under a progressive ratio reinforcement schedule, there was no increase in dopamine release to drug rewards across trials, which contrasts with prior studies demonstrating an increase in dopamine release to food rewards. Collectively, these findings illustrate that the influence of operant costs on reward-evoked dopamine release depends upon type of reward that can be earned (e.g., food or drug).SIGNIFICANCE STATEMENT The mesolimbic dopamine system is involved with mediating drug reinforcement. Although the costs associated with earning drugs are dynamic, no studies to date have examined how dopamine release to drug rewards is affected by changing costs. By performing fast-scan cyclic voltammetry recordings in rats self-administering cocaine, the present work demonstrates that changing the operant costs reversibly modulates the dopamine response to cocaine rewards. Furthermore, these findings highlight that the influence of costs on dopamine release to drug rewards differs from the established effect of costs on dopamine release to food rewards.

Mesencephalic dopamine neurons interfacing the shell of nucleus accumbens and the dorsolateral striatum in the rat.

Parallel corticostriatonigral circuits have been proposed that separately process motor, cognitive, and emotional‐motivational information. Functional integration requires that interactions exist between neurons participating in these circuits. This makes it imperative to study the complex anatomical substrate underlying corticostriatonigral circuits. It has previously been proposed that dopaminergic neurons in the ventral mesencephalon may play a role in this circuit interaction. Therefore, we studied in rats convergence of basal ganglia circuits by depositing an anterograde neuroanatomical tracer into the ventral striatum together with a retrograde fluorescent tracer ipsilaterally in the dorsolateral striatum. In the mesencephalon, using confocal microscopy, we looked for possible appositions of anterogradely labeled fibers and retrogradely labeled neurons, “enhancing” the latter via intracellular injection of Lucifer Yellow. Tyrosine hydroxylase (TH) immunofluorescence served to identify dopaminergic neurons. In neurophysiological experiments, we combined orthodromic stimulation in the medial ventral striatum with recording from ventral mesencephalic neurons characterized by antidromic stimulation from the dorsal striatum. We observed terminal fields of anterogradely labeled fibers that overlap populations of retrogradely labeled nigrostriatal cell bodies in the substantia nigra pars compacta and lateral ventral tegmental area (VTA), with numerous close appositions between boutons of anterogradely labeled fibers and nigrostriatal, TH‐immunopositive neurons. Neurophysiological stimulation in the medial ventral striatum caused inhibition of dopaminergic nigrostriatal neurons projecting to the ventrolateral striatal territory. Responding nigrostriatal neurons were located in the medial substantia nigra and adjacent VTA. Our results strongly suggest a functional link between ventromedial, emotional‐motivational striatum, and the sensorimotor dorsal striatum via dopaminergic nigrostriatal neurons.

Dissociable effects of antipsychotics on ketamine-induced changes in regional oxygenation and inter-regional coherence of low frequency oxygen fluctuations in the rat.

Typical and atypical antipsychotics have been shown to alleviate N-methyl-D-aspartate (NMDA) receptor antagonist-induced BOLD signals in healthy humans and animals to differing degrees; factors that might relate to their different molecular mechanisms and clinical profiles. Recent studies have also extended these investigations to the analysis of resting state functional connectivity measures of BOLD signals in different brain regions. Using constant potential amperometry, we examined the effects of the NMDA receptor antagonist S-(+)-ketamine on tissue oxygen levels in medial prefrontal cortex (mPFC) and medial ventral striatum (mVS), and temporal coherence of low-frequency oxygen fluctuations between these regions in freely moving rats. Furthermore, we assessed the extent to which the atypical antipsychotic clozapine and the typical antipsychotic haloperidol could modulate the effects of S-(+)-ketamine on these measures. Acute S-(+)-ketamine (5-25 mg/kg) produced dose-dependent increases in both tissue O2 levels and coherence. Although effects of clozapine and haloperidol alone were relatively minor, their effects on ketamine-induced signals were markedly more distinct. Clozapine dose-dependently attenuated the absolute S-(+)-ketamine (25 mg/kg) O2 signal in both regions, and also attenuated ketamine-induced increases in regional coherence. Haloperidol had no effect on the absolute ketamine O2 signal yet potentiated increases in regional coherence. The dissociable effects of haloperidol and clozapine on ketamine-induced hyperoxygenation and mPFC-mVS coherence elucidate potentially important mechanistic differences between these classes of pharmacology. This study demonstrates for the first time that in vivo amperometry can measure both regional brain tissue O2 levels and inter-regional coherence, advancing BOLD-like measurements of functional connectivity into awake, unconstrained animals.

Adenosine’s Autacoid Function in the Central Nervous System and the Behavioral State of Conservation-Withdrawal

The purine nucleoside adenosine has the critical autacoid function of directly linking cellular excitability to energy availability. The mechanism is activated whenever the rate of adenosine triphosphate (ATP) utilization exceeds the rate of synthesis. In CNS neurons, adenosine is produced by the rapid intracellular hydrolysis of purine nucleotides during neural excitation and then is extruded into extracellular space. The nucleoside is also produced by the extracellular hydrolysis of ATP by ectonucleotidases. Extracellular adenosine interacts with G-protein linked stereospecific receptors to reestablish metabolic homeostasis by exerting extraordinarily potent inhibition of neural excitation via a number of mechanisms. This autacoid mechanism is directly linked to the production of a depression like behavioral state termed conservation-withdrawal during times of physical stress or severe emotional distress. We review evidence here that adenosine produces a transition to conservation-withdrawal by activation of A2A receptors in the ventral-medial striatum.

Newly paired zebra finches have higher dopamine levels and immediate early gene Fos expression in dopaminergic neurons

Most birds are socially monogamous, yet little is known about the neural pathways underlying avian monogamy. Recent studies have implicated dopamine as playing a role in courtship and affiliation in a socially monogamous songbird, the zebra finch (Taeniopygia guttata). In the present study, we sought to understand the specific contribution to pair formation in zebra finches of the mesolimbic dopaminergic pathway that projects from the midbrain ventral tegmental area to the nucleus accumbens. We observed that paired birds had higher levels of dopamine and its metabolite 3,4-dihydroxyphenylacetic acid in the ventral medial striatum, where the nucleus accumbens is situated, than unpaired birds. Additionally, we found that the percentage of dopaminergic neurons expressing immediate early gene Fos, a marker of neuronal activity, was higher in the ventral tegmental area of paired birds than in that of unpaired birds. These data are consistent with a role for the mesolimbic dopaminergic pathway in pair formation in zebra finches, suggesting the possibility of a conserved neural mechanism of monogamy in birds and mammals.

Closing the Gate in the Limbic Striatum: Prefrontal Suppression of Hippocampal and Thalamic Inputs

Many brain circuits control behavior by integrating information arising from separate inputs onto a common target neuron. Neurons in the ventral striatum (VS) receive converging excitatory afferents from the prefrontal cortex (PFC), hippocampus (HP), and thalamus, among other structures, and the integration of these inputs is critical for goal-directed behaviors. Although HP inputs have been described as gating PFC throughput in the VS, recent data reveal that the VS desynchronizes from the HP during epochs of burst-like PFC activity related to decision making. It is therefore possible that PFC inputs locally attenuate responses to other glutamatergic inputs to the VS. Here, we found that delivering trains of stimuli to the PFC suppresses HP- and thalamus-evoked synaptic responses in the VS, in part through activation of inhibitory processes. This interaction may enable the PFC to exert influence on basal ganglia loops during decision-making instances with minimal disturbance from ongoing contextual inputs.

Ventral striatal anatomy of locomotor activity induced by cocaine, D-amphetamine, dopamine and D 1/D 2 agonists

The ventral striatum appears to play a critical role in mediating motoric effects (i.e. ambulatory activity and rearing) of psychostimulants such as cocaine. We evaluated whether sub-regions of the ventral striatum play differential roles in locomotion and rearing induced by various dopaminergic drugs. Injections of D-amphetamine and dopamine stimulated locomotion and rearing with a similar potency at each of the sub-regions: the core, medial shell or medial tubercle. However, injections of mixtures of the D 1- and D 2-type agonists SKF 38393 and quinpirole or cocaine into the medial olfactory tubercle or the medial shell of the nucleus accumbens induced marked locomotion and rearing, while these injections into the core induced little or no locomotion or rearing. Furthermore, cocaine injections into the lateral or posterior tubercle produced marginal locomotion and rearing, while cocaine injections into regions just dorsal to these tubercle sites, the lateral portion of the shell or the ventral pallidum, did not produce any stimulating effect. We conclude that dopaminergic compounds induce vigorous locomotion and rearing in both core and shell; the relative roles of the core and shell differ depending on chemical compounds. Similar to the nucleus accumbens, the olfactory tubercle, particularly the medial portion, also mediates these behaviors induced by dopaminergic compounds. The medial ventral striatum (i.e. the medial tubercle and medial shell) plays a more important role in cocaine-induced locomotion and rearing than the lateral ventral striatum (i.e. the core, lateral shell and lateral tubercle). Moreover, the differential effects of cocaine between the medial and lateral portions of the shell on locomotion and rearing suggest more than two functional units (the core vs. the shell) within the accumbens.

Use of Wheat Gluten as Clarifying Agent of Musts and White Wines

The ventral striatum is considered an interface between limbic and motor systems. We followed the orbital and medial prefrontal circuit through the monkey basal ganglia by analyzing the projection from this cortical area to the ventral striatum and the representation of orbitofrontal cortex via the striatum, in the globus pallidus and substantia nigra. Following injections of Lucifer yellow and horse radish peroxidase into the medial ventral striatum, there is a very densely labeled distribution of cells in areas 13a and 13b, primarily in layers V and VI, and in medial prefrontal areas 32 and 25. Injections into the shell of the nucleus accumbens labeled primarily areas 25 and 32. The reaction product in the globus pallidus and the substantia nigra supports previous studies demonstrating that efferent projections from the ventral striatum are represented topographically in the ventral pallidum and nontopographically in the substantia nigra, pars compacta. Tritiated amino acid or PHA-L tracer injections into orbitofrontal cortex produce dense patches of terminal labeling along the medial edge of the caudate nucleus and the dorsal part of the nucleus accumbens. These results demonstrate that the orbital prefrontal cortex projects primarily to the medial edge of the ventral striatum and to the core of the nucleus accumbens. The arrangement of terminals in the globus pallidus and substantia nigra show two different patterns. Thus, the orbital and medial prefrontal cortex is represented in a confined region of the globus pallidus but throughout an extensive area of the dorsal substantia nigra. Terminals are extensive throughout the region of the dopaminergic neurons, suggesting that this input may influence a wide area of both the striatum and frontal cortex.

Insular Cortical Projections to Functional Regions of the Striatum Correlate with Cortical Cytoarchitectonic Organization in the Primate

We examined the striatal projections from different cytoarchitectonic regions of the insular cortex using anterograde and retrograde techniques. The shell and medial ventral striatum receive inputs primarily from the agranular and ventral dysgranular insula. The central ventral striatum receives inputs primarily from the dorsal agranular and dysgranular insula. Projections to the central ventral striatum originate from more posterior and dorsal insular regions than projections to the medial ventral striatum. The dorsolateral striatum receives projections primarily from the dorsal dysgranular and granular insula. These results show that cytoarchitectonically less differentiated (agranular) insular regions project to the ventromedial "limbic" part of the ventral striatum, whereas more differentiated (granular) insular regions project to the dorsolateral "sensorimotor" part of the striatum. The finding that the ventral "limbic" striatum receives inputs from less differentiated regions of the insula is consistent with the general principle that less differentiated cortical regions project primarily to the "limbic" striatum. Functionally, the ventral striatum receives insular projections primarily related to integrating feeding behavior with rewards and memory, whereas the dorsolateral striatum receives insular inputs related to the somatosensation. Information regarding food acquisition in the insula may be sent to the intermediate area of the striatum.

The orbital and medial prefrontal circuit through the primate basal ganglia

The ventral striatum is considered an interface between limbic and motor systems. We followed the orbital and medial prefrontal circuit through the monkey basal ganglia by analyzing the projection from this cortical area to the ventral striatum and the representation of orbitofrontal cortex via the striatum, in the globus pallidus and substantia nigra. Following injections of Lucifer yellow and horse radish peroxidase into the medial ventral striatum, there is a very densely labeled distribution of cells in areas 13a and 13b, primarily in layers V and VI, and in medial prefrontal areas 32 and 25. Injections into the shell of the nucleus accumbens labeled primarily areas 25 and 32. The reaction product in the globus pallidus and the substantia nigra supports previous studies demonstrating that efferent projections from the ventral striatum are represented topographically in the ventral pallidum and nontopographically in the substantia nigra, pars compacta. Tritiated amino acid or PHA-L tracer injections into orbitofrontal cortex produce dense patches of terminal labeling along the medial edge of the caudate nucleus and the dorsal part of the nucleus accumbens. These results demonstrate that the orbital prefrontal cortex projects primarily to the medial edge of the ventral striatum and to the core of the nucleus accumbens. The arrangement of terminals in the globus pallidus and substantia nigra show two different patterns. Thus, the orbital and medial prefrontal cortex is represented in a confined region of the globus pallidus but throughout an extensive area of the dorsal substantia nigra. Terminals are extensive throughout the region of the dopaminergic neurons, suggesting that this input may influence a wide area of both the striatum and frontal cortex.

Withdrawal from morphine or amphetamine: different effects on dopamine in the ventral-medial striatum studied with microdialysis

The effect of withdrawal from chronic morphine or amphetamine treatment on dopamine (DA) neurotransmission in the ventral-medial striatum was studied by use of in vivo microdialysis. There was no effect of 24 h of amphetamine withdrawal on the basal concentration of DA in the ventral-medial striatum. Spontaneous morphine withdrawal (24 h) was associated with a significant decrease in the basal concentration of DA in dialysate, but following morphine replacement and naloxone-precipitated withdrawal variations in withdrawal symptoms were not related to variations in the concentration of DA in dialysate. It is suggested that: (1) the correlation between the extracellular concentration of DA in the ventral-medial striatum and the symptoms of morphine withdrawal may not be indicative of a necessary, causal relationship; and (2) a decrease in the extracellular concentration of DA in the ventral-medial striatum is not a common feature of drug withdrawal syndromes.

Spatial, movement- and reward-sensitive discharge by medial ventral striatum neurons of rats

Previous behavioral and acute electrophysiological data have lead researchers to speculate that the nucleus accumbens integrates limbic, reward and motor information [5,12,22,31]. The present study examined the behavioral correlates to single unit activity of the nucleus accumbens and surrounding ventral striatum as a means of evaluating the integrative functioning of this region in an awake animal. Medial ventral striatum (mVS) activity was recorded as rats completed multiple trials on an eight arm radial maze. Neuronal activity was found to correlate with spatial, reward- and movement-related behavioral conditions. While the majority of cells demonstrated correlates of a single type (i.e. either spatial or reward correlates), 6 cells encoded multiple correlates of different types (i.e. spatial and reward correlates). The data suggests that this integrative process can be active both at the level of the individual neuron, and at the structural level. These results are consistent with the hypothesis that the mVS integrates spatial and reward-related information, which in turn influences voluntary motor output structures in order to achieve accurate navigational behavior.