Activity Of Dopamine Neurons Research Articles

Reproducing the dopamine pathophysiology of schizophrenia and approaches to ameliorate it: a translational imaging study with ketamine

Patients with schizophrenia show increased striatal dopamine synthesis capacity in imaging studies. The mechanism underlying this is unclear but may be due to N-methyl-D-aspartate receptor (NMDAR) hypofunction and parvalbumin (PV) neuronal dysfunction leading to disinhibition of mesostriatal dopamine neurons. Here, we develop a translational mouse model of the dopamine pathophysiology seen in schizophrenia and test approaches to reverse the dopamine changes. Mice were treated with sub-chronic ketamine (30 mg/kg) or saline and then received in vivo positron emission tomography of striatal dopamine synthesis capacity, analogous to measures used in patients. Locomotor activity was measured using the open-field test. In vivo cell-type-specific chemogenetic approaches and pharmacological interventions were used to manipulate neuronal excitability. Immunohistochemistry and RNA sequencing were used to investigate molecular mechanisms. Sub-chronic ketamine increased striatal dopamine synthesis capacity (Cohen’s d = 2.5) and locomotor activity. These effects were countered by inhibition of midbrain dopamine neurons, and by activation of PV interneurons in pre-limbic cortex and ventral subiculum of the hippocampus. Sub-chronic ketamine reduced PV expression in these cortical and hippocampal regions. Pharmacological intervention with SEP-363856, a novel psychotropic agent with agonism at trace amine receptor 1 (TAAR1) and 5-HT1A receptors but no appreciable action at dopamine D2 receptors, significantly reduced the ketamine-induced increase in dopamine synthesis capacity. These results show that sub-chronic ketamine treatment in mice mimics the dopaminergic alterations in patients with psychosis, that this requires activation of midbrain dopamine neurons, and can be ameliorated by activating PV interneurons and by a TAAR1/5-HT1A agonist. This identifies novel therapeutic approaches for targeting presynaptic dopamine dysfunction in patients with schizophrenia and effects of ketamine relevant to its therapeutic use for treating major depression.

Paranigral VTA Nociceptin Neurons Constrain Motivation for Reward

Nociceptin and the nociceptin opioid peptide (NOP) receptor are widely distributed throughout the brain and have been proposed to have an endogenous role in regulating motivational state; however, how this regulation may occur remains unresolved. NOP receptors are broadly expressed in ventral tegmental area (VTA) dopamine neurons and their activation inhibits dopamine neuron activity, yet the behavioral consequences of this neuropeptide system’s impact in the VTA are unknown. Here we dissected the role of a VTA nociceptin peptide circuit that constrains reward-seeking behavior.

Postingestive Modulation of Food Seeking Depends on Vagus-Mediated Dopamine Neuron Activity

SummaryPostingestive nutrient sensing can induce food preferences. However, much less is known about the ability of postingestive signals to modulate food-seeking behaviors. Here we report a causal connection between postingestive sucrose sensing and vagus-mediated dopamine neuron activity in the ventral tegmental area (VTA), supporting food seeking. The activity of VTA dopamine neurons increases significantly after administration of intragastric sucrose, and deletion of the NMDA receptor in these neurons, which affects bursting and plasticity, abolishes lever pressing for postingestive sucrose delivery. Furthermore, lesions of the hepatic branch of the vagus nerve significantly impair postingestive-dependent VTA dopamine neuron activity and food seeking, whereas optogenetic stimulation of left vagus nerve neurons significantly increases VTA dopamine neuron activity. These data establish a necessary role of vagus-mediated dopamine neuron activity in postingestive-dependent food seeking, which is independent of taste signaling.

Beta‐caryophyllene, a Volatile Phytocannabinoid, Attenuates Cocaine Self‐administration and Relapse in Rats

Cocaine abuse continues to be a serious health problem worldwide. Despite intense research, there is still no FDA‐approved medication to treat cocaine use disorder. The recent search for effective therapeutics has been focused on the endocannabinoid system because of its critical role in the neurobiology of drug addiction. In the last decade, there has been a growing interest in beta‐caryophyllene (BCP), a volatile phytocannabinoid present in high proportions in cannabis and large number of spice and food plants including black pepper, thyme and cloves. This dietary additive that has a CB2 receptor (CB2R) agonist profile, has shown to produce promising therapeutic effects for multiple neuropsychiatric disorders. Surprisingly, the therapeutic potential of BCP in the treatment of drug abuse and addiction has not been explored. Here, using gold standard animal models of drug abuse, we systematically evaluated the potential utility of BCP against cocaine‐related behaviors in rodents and its mechanisms of action. In a series of experiments we found that BCP attenuated cocaine‐enhanced electrical brain‐stimulation reward and optogenetic intracranial self‐stimulation driven by activation of dopamine (DA) neurons in DAT‐cre mice, both outcomes indicating reduced reward. Intriguingly, when administered systemically or orally, BCP attenuated cocaine self‐administration in rats, suggesting an ability to reduce drug abuse. BCP also reduced drug‐primed reinstatement of cocaine seeking and cocaine conditioned place preference, indicative of its preventative effects against relapse. When BCP was substituted for cocaine, rats ceased responding, suggesting BCP has low liability abuse. In regards to the receptor mechanisms, our pharmacological approach (along with our transgenic approach utilizing with CB1, CB2, GPR55 knockout mice) indicates that BCP produces attenuating effects on cocaine self‐administration that are mediated by non‐cannabinoid receptors. We are now exploring the involvement of peroxisome proliferator‐activated receptor (PPAR) and transient receptor potential vanilloid 1 cation channels (TRPV1) in BCP action against cocaine. Our findings suggest that BCP shows exceptional promise as a therapeutic candidate in the treatment of cocaine use disorder. Importantly, given its good oral bioavailability and the advantage of being an already FDA‐approved non‐toxic dietary additive, BCP is a valuable candidate for drug repurposing programs in translational medicine.

Effects of ghrelin receptor activation on forebrain dopamine release, conditioned fear and fear extinction in C57BL/6J mice.

The ghrelin system was previously proposed to mediate an independent branch of the stress response that curbs fear processing. Interestingly, the ghrelin system was also shown to control the activity of midbrain dopamine neurons. Given that dopamine neurons of the ventral tegmental area appear to have a critical role in fear processing, we aimed to investigate their contribution to the effects of ghrelin on fear processing. Our data show that systemic administration of the ghrelin receptor agonist MK0677, in a dose that induces food intake, has no significant effect on auditory fear processing and does not significantly affect dopamine release in the nucleus accumbens of male C57BL/6J mice. Local administration of the ghrelin receptor agonist MK0677 into the ventral tegmental area significantly increases food intake and it also significantly increased dopamine release in the nucleus accumbens, the medial prefrontal cortex and the amygdala. Nevertheless, it did not significantly affect auditory fear extinction. Our data indicate that pharmacological activation of midbrain dopamine neurons using a ghrelin receptor agonist does not affect auditory fear extinction. We also investigated the effect of non-pharmacological manipulation of the ghrelin system on auditory fear processing. However, we found that neither overnight food deprivation nor genetic ablation of the ghrelin receptor had a significant effect on auditory fear extinction. We conclude that the effects of manipulation of the ghrelin system on fear processing are subject to boundary conditions that remain poorly understood.

Hyperexcitability of VTA dopaminergic neurons in male offspring exposed to physical or psychological prenatal stress

Prenatal stress (PS) exposure leads to cognitive and behavioral alterations in offspring including an increased risk of substance abuse and anxiety disorders. Signalling from dopamine (DA) neurons of the ventral tegmental area (VTA) in the mesoaccumbal and mesocortical pathways plays a vital role in drug dependency and anxiety behavior. To provide further knowledge about the changes in drug seeking behavior and anxiety behaviors in prenatally stressed mice, we conducted ex vivo investigations in VTA brain slices of adult male PS offspring to evaluate the effects of two types of PS (physical vs. psychological) on activity of DA neurons. Elevated plus maze (EPM) was used to assess anxiety-like behaviors and conditioned place preference (CPP) was used to evaluate drug reinforcing effects in mice. An increased anxiety-like behavior and preference to morphine was observed in prenatally stressed mice. PS VTA DA cells exhibited greater Ih current and a higher frequency and amplitude of sEPSCs, which were consistent with a greater degree of pre- or postsynaptic excitability of the VTA. This was confirmed by lower rheobase and lower firing thresholds in PS VTA neurons, as well as increases in spontaneous firing frequency. When taken together, these data suggest that alterations in VTA DA neurons in this mouse model of prenatal stress might be associated with later life alterations in drug seeking and anxiety-like behaviors through their role in mesocortical and mesoaccumbal pathways.

Histone deacetylase inhibition reduces ventral tegmental area dopamine neuronal hyperexcitability involving AKAP150 signaling following maternal deprivation in juvenile male rats.

Traumatic early life stress (ELS) is linked to dopamine (DA) dysregulation which increases the probability of developing psychiatric disorders in adolescence and adulthood. Our prior studies demonstrated that a severe early life stressor, a 24-hr maternal deprivation (MD) in juvenile male rats, could lead to altered DA signaling from the ventral tegmental area (VTA) due to impairment of GABAergic synaptic plasticity (promoting GABAergic long-term depression, LTD) with concomitant changes in the abundance of synaptic regulators including A-kinase anchoring protein (AKAP150). Importantly, these MD-induced synaptic changes in the VTA were accompanied by upregulation of histone deacetylase 2, histone hypoacetylation, and were reversible by HDAC inhibition. Using cell-attached and whole-cell patch clamp recordings, we found that MD stress also increased spontaneous VTA DA neuronal activity and excitability in juvenile male rats without affecting intrinsic excitability. Postsynaptic chemical disruption of AKAP150 and protein kinase A interaction increased VTA DA neuronal excitability in control non-MD rats mimicking the effects of MD on DA cell excitability with similar changes in membrane properties. Interestingly, this disruption decreased MD-induced VTA DA hyperexcitability. This MD-induced DA neuronal hyperexcitability could also be normalized at 24hr after injection of the class 1 HDAC inhibitor, CI-994. Altogether, our data suggest that AKAP150 plays a critical role in the regulation of VTA DA neuronal excitability and that HDAC-mediated targeting of AKAP150 signaling could normalize VTA DA dysfunction following ELS thereby providing novel therapeutic targets for prevention of later life psychopathology.

Crosstalk Between Kappa Opioid and Dopamine Systems in Compulsive Behaviors.

The strength of goal-oriented behaviors is regulated by midbrain dopamine neurons. Dysfunctions of dopaminergic circuits are observed in drug addiction and obsessive-compulsive disorder. Compulsive behavior is a feature that both disorders share, which is associated to a heightened dopamine neurotransmission. The activity of midbrain dopamine neurons is principally regulated by the homeostatic action of dopamine through D2 receptors (D2R) that decrease the firing of neurons as well as dopamine synthesis and release. Dopamine transmission is also regulated by heterologous neurotransmitter systems such as the kappa opioid system, among others. Much of our current knowledge of the kappa opioid system and its influence on dopamine transmission comes from preclinical animal models of brain diseases. In 1988, using cerebral microdialysis, it was shown that the acute activation of the Kappa Opioid Receptors (KOR) decreases synaptic levels of dopamine in the striatum. This inhibitory effect of KOR opposes to the facilitating influence of drugs of abuse on dopamine release, leading to the proposition of the use of KOR agonists as pharmacological therapy for compulsive drug intake. Surprisingly, 30 years later, KOR antagonists are instead proposed to treat drug addiction. What may have happened during these years that generated this drastic change of paradigm? The collected evidence suggested that the effect of KOR on synaptic dopamine levels is complex, depending on the frequency of KOR activation and timing with other incoming stimuli to dopamine neurons, as well as sex and species differences. Conversely to its acute effect, chronic KOR activation seems to facilitate dopamine neurotransmission and dopamine-mediated behaviors. The opposing actions exerted by acute versus chronic KOR activation have been associated with an initial aversive and a delayed rewarding effect, during the exposure to drugs of abuse. Compulsive behaviors induced by repeated activation of D2R are also potentiated by the sustained co-activation of KOR, which correlates with decreased synaptic levels of dopamine and sensitized D2R. Thus, the time-dependent activation of KOR impacts directly on dopamine levels affecting the tuning of motivated behaviors. This review analyzes the contribution of the kappa opioid system to the dopaminergic correlates of compulsive behaviors.

Cue-Evoked Dopamine Promotes Conditioned Responding during Learning

Dopamine neurons mediate the association of conditioned stimuli (CS) with reward (unconditioned stimuli, US) by signaling the discrepancy between predicted and actual reward during the US. Some theoretical models suggest that learning is also influenced by the salience or associability of the CS. A hallmark of CS associability models is that they can explain latent inhibition, i.e., the observation that novel CS are more effectively learned than familiar CS. Novel CS are known to activate dopamine neurons, but whether those responses affect associative learning has not been investigated. Here, we used fiber photometry to characterize dopamine responses to inconsequential familiar and novel stimuli. Using bidirectional optogenetic modulation during conditioning, we then show that CS-evoked dopamine promotes conditioned responses. This suggests that Pavlovian conditioning is influenced by CS dopamine, in addition to US reward prediction errors. Accordingly, the absence of dopamine responses to familiar CS might explain their slower learning in latent inhibition.

P.222 Ghrelin enhances dopamine neuronal activity in the ventral tegmental area during food prediction but not consumption

Pharmacological inhibition of the enzyme fatty acid amide hydrolase (FAAH), which terminates signaling of the endocannabinoid N-arachidonoylethanolamine (or anandamide, AEA), exerts favourable effects in rodent models of stress-related depression. Yet although depression seems to be more common among women than men and in spite of some evidence of sex differences in treatment efficacy, preclinical development of FAAH inhibitors for the pharmacotherapy of stress-related depression has been predominantly conducted in male animals. Here, adult female rats were exposed to six weeks of social isolation and, starting from the second week, treated with the FAAH inhibitor URB694 (0.3 mg/kg/day, i.p.) or vehicle. Compared to pair-housed females, socially isolated female rats treated with vehicle developed behavioral (mild anhedonia, passive stress coping) and physiological (reduced body weight gain, elevated plasma corticosterone levels) alterations. Moreover, prolonged social isolation provoked a reduction in brain-derived neurotrophic factor (BDNF) and AEA levels within the hippocampus. Together, these changes are indicative of an increased risk of developing a depressive-like state. Conversely, pharmacological inhibition of FAAH activity with URB694 restored both AEA and BDNF levels within the hippocampus of socially isolated rats and prevented the development of behavioral and physiological alterations. These results suggest a potential interplay between AEA-mediated signaling and hippocampal BDNF in the pathogenesis of depression-relevant behaviors and physiological alterations and antidepressant action of FAAH inhibition in socially isolated female rats.

Endocannabinoids mediate long-lasting behavioural and physiological changes in male rats induced by the repeated activation of the mesolimbic system by copulation to satiety

Sexually satiated male rats exhibit long-lasting physiological changes, suggestive of brain plasticity, the most conspicuous of which are a sexual behaviour inhibition and a generalised drug hypersensitivity. Copulation activates the mesolimbic circuit increasing dopamine (DA) release in the nucleus accumbens (NAcc) and, enhanced midbrain DA neuron activity promotes endocannabinoid (eCB) release in the ventral tegmental area (VTA). The objective of this work was to explore the possible participation of DA and/or eCB transmission in the induction of these two long-lasting phenomena. To this aim we analysed the effect of blocking DA or CB1 receptors during the process of copulation to exhaustion, on the expression 24 h later, of the sexual inhibitory state and the hypersensitivity to two different drugs: 8-OH-DPAT, a 5-HT1A receptor agonist, and yohimbine, an α2-adrenoceptor antagonist. Blockade of DA receptors failed to prevent these phenomena, while blockade of CB1 receptors interfered with the appearance of the sexual inhibition and the hypersensitivity to both drugs in the sexually satiated animals. Specific blockade of CB1 receptors in the VTA during copulation to satiety mimicked these results, suggesting that both eCB-mediated effects were exerted in this brain region. It is concluded that eCBs play a role in the induction of behavioural and physiological changes, triggered by copulation to satiety, by acting at the VTA, while increased NAcc DA levels appear not to contribute to the changes induced by intense copulation. Results pose sexual satiety as a useful model for the study of brain plasticity phenomena induced by natural rewards.

The Lateral Preoptic Area: A Novel Regulator of Reward Seeking and Neuronal Activity in the Ventral Tegmental Area.

The lateral preoptic area (LPO) is a hypothalamic region whose function has been largely unexplored. Its direct and indirect projections to the ventral tegmental area (VTA) suggest that the LPO could modulate the activity of the VTA and the reward-related behaviors that the VTA underlies. We examined the role of the LPO on reward taking and seeking using operant self-administration of cocaine or sucrose. Rats were trained to self-administer cocaine or sucrose and then subjected to extinction, whereby responding was no longer reinforced. We tested if stimulating the LPO pharmacologically with bicuculline or chemogenetically with Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) modifies self-administration and/or seeking. In another set of experiments, we tested if manipulating the LPO influences cocaine self-administration during and after punishment. To examine the functional connectivity between the LPO and VTA, we used in vivo electrophysiology recordings in anesthetized rats. We tested if stimulating the LPO modifies the activity of GABA and dopamine neurons of the VTA. We found that stimulating the LPO reinstated cocaine and sucrose seeking behavior but had no effect on reward intake. Furthermore, both stimulating and inhibiting the LPO prevented the sustained reduction in cocaine intake seen after punishment. Finally, stimulating the LPO inhibited the activity of VTA GABA neurons while enhancing that of VTA dopamine neurons. These findings indicate that the LPO has the capacity to drive reward seeking, modulate sustained reductions in self-administration following punishment, and regulate the activity of VTA neurons. Taken together, these findings implicate the LPO as a previously overlooked member of the reward circuit.

Dopamine transients do not act as model-free prediction errors during associative learning

Dopamine neurons are proposed to signal the reward prediction error in model-free reinforcement learning algorithms. This term represents the unpredicted or ‘excess’ value of the rewarding event, value that is then added to the intrinsic value of any antecedent cues, contexts or events. To support this proposal, proponents cite evidence that artificially-induced dopamine transients cause lasting changes in behavior. Yet these studies do not generally assess learning under conditions where an endogenous prediction error would occur. Here, to address this, we conducted three experiments where we optogenetically activated dopamine neurons while rats were learning associative relationships, both with and without reward. In each experiment, the antecedent cues failed to acquire value and instead entered into associations with the later events, whether valueless cues or valued rewards. These results show that in learning situations appropriate for the appearance of a prediction error, dopamine transients support associative, rather than model-free, learning.

Dopamine-Producing Neurons in Rat Ontogeny: Phenotypic Features Underlying Molecular Mechanisms of Secretion and Regulation

Dopamine (DA), which is synthesized in DA-ergic neurons and so-called monoenzymatic neurons, is involved in the regulation of neuronal differentiation during the critical period of morphogenesis. The aim of the present study was to examine phenotypic features of DA-producing neurons in several brain regions, including the striatum, suprachiasmatic nucleus, and arcuate nucleus, during rat ontogeny starting from embryonic day 18 (E18) to postnatal day 60 (P60). The enzymes of DA synthesis tyrosine hydroxylase (TH) and aromatic amino acid decarboxylase (AAAD), vesicular monoamine transporters (VMAT), and D1 and D2 DA receptors were used as markers for functional activity of DA neurons. Expression of these markers was studied using double immunohistochemical labeling of TH and AAAD or PCR assay of TH, AAAD, VMAT1, VMAT2, and D1 and D2 DA receptors. In the striatum, mRNAs of all mentioned markers were revealed within the whole period of ontogeny studied, bienzymatic TH and AAAD-immunopositive neurons were observed at E18, whereas monoenzymatic TH- or AAAD-containing neurons were observed at P60 only. In the suprachiasmatic nucleus, monoenzymatic AAAD neurons coexist with monoenzymatic TH-immunoreactive fibers, which innervate the ventral part of the nucleus, in the early postnatal period (P10). At P10 in the suprachiasmatic nucleus, the TH, VMAT1, and VMAT2 genes are not expressed; however, transcripts of the D1 and D2 genes were detected. The arcuate nucleus of rat embryos contained only monoenzymatic TH neurons in the ventrolateral area and AAAD neurons in the dorsomedial area in the late prenatal period (E21). At the same time TH, AAAD, VMAT2, D1, and D2 mRNAs were expressed in both parts of the arcuate nucleus. Thus, during rat ontogeny, nondopaminergic neurons containing one of the enzymes, TH or AAAD, are present in the striatum, suprachiasmatic nucleus, and arcuate nucleus, which allows for suggesting the cooperative synthesis of dopamine in these brain structures.

Dopaminergic and Prefrontal Basis of Learning from Sensory Confidence and Reward Value

SummaryDeciding between stimuli requires combining their learned value with one’s sensory confidence. We trained mice in a visual task that probes this combination. Mouse choices reflected not only present confidence and past rewards but also past confidence. Their behavior conformed to a model that combines signal detection with reinforcement learning. In the model, the predicted value of the chosen option is the product of sensory confidence and learned value. We found precise correlates of this variable in the pre-outcome activity of midbrain dopamine neurons and of medial prefrontal cortical neurons. However, only the latter played a causal role: inactivating medial prefrontal cortex before outcome strengthened learning from the outcome. Dopamine neurons played a causal role only after outcome, when they encoded reward prediction errors graded by confidence, influencing subsequent choices. These results reveal neural signals that combine reward value with sensory confidence and guide subsequent learning.

P.059 The association between the polygenic risk score for bipolar disorder and school grades

Neuroimaging and preclinical studies showing that nicotinic receptors (nAChR) may play a role in mood control has increased interest in targeting the cholinergic system for treatment of major depressive disorder. Indeed, modulation of nAChRs in the basolateral amygdala (BLA) are sufficient to produce an anti-immobility effect in the mouse tail suspension test. However, how α7 nAChR modulation impacts BLA neuronal activity in vivo as well as the downstream mechanisms involved in its mood-related effects are not understood. In this work, we used the unpredictable chronic mild stress (CMS) model to investigate the mechanisms underlying the antidepressant-like effect of an α7 nAChR full agonist on BLA-induced changes in dopaminergic neurotransmission. Male adult Sprague-Dawley rats were exposed to four weeks of CMS. Behavioral and electrophysiological experiments were performed within one week following stress. CMS exposure increased rats’ immobility time in the forced swimming test, decreased the number of spontaneously active dopamine neurons in the ventral tegmental area and increased the firing rate of putative projection neurons in the BLA. Stress-induced behavioral and electrophysiological changes were reversed by a single systemic administration of PNU282987. In summary, our findings corroborate previous descriptions of a potential rapid antidepressant effect for the α7 nAChR full agonist. This effect appears to involve a mechanism distinct from those of classic antidepressants: normalization of BLA hyperactivity and, consequently, of DA hypofunction. These observations corroborate the role of α7 nAChR as a potential target for novel antidepressant drug development.

Neurotensin receptor 1 deletion decreases methamphetamine self-administration and the associated reduction in dopamine cell firing.

We previously reported that a non-selective pharmacological blockade of neurotensin receptors in the ventral tegmental area (VTA) decreases methamphetamine (METH) self-administration in mice. Here, we explored the consequences of genetic deletion of neurotensin receptor 1 (NtsR1) on METH self-administration and VTA dopamine neuron firing activity. We implanted mice with an indwelling jugular catheter and trained them to nose-poke for intravenous infusions of METH. Mice with NtsR1 deletion (KO) acquired self-administration similar to wildtype (WT) and heterozygous (HET) littermates. However, in NtsR1 KO and HET mice, METH intake and motivated METH seeking decreased when the response requirement was increased to a fixed ratio 3 and when mice were tested on a progressive ratio protocol. After completion of METH self-administration, single cell in vivo extracellular recordings of dopamine firing activity in the VTA were obtained in anesthetized mice. Non-bursting dopamine neurons from KO mice fired at slower rates than those from WT mice, supporting an excitatory role for NtsR1 on VTA dopamine neuronal activity. In WT mice, a history of METH self-administration decreased dopamine cell firing frequency compared with cells from drug-naïve controls. NtsR1 KO and HET mice did not exhibit this decline in dopamine cell firing activity after METH experience. We also observed an increase in population activity following METH self-administration that was strongest in the WT group. Our results suggest a role for NtsR1 in METH-seeking behavior and indicate that ablation of NtsR1 prevents the detrimental effects of prolonged METH self-administration on VTA dopamine cell firing frequency.

Cue-Evoked Dopamine Neuron Activity Helps Maintain but Does Not Encode Expected Value

Cue-evoked midbrain dopamine (DA) neuron activity reflects expected value, but its influence on reward assessment is unclear. In mice performing a trial-based operant task, we test if bidirectional manipulations of cue or operant-associated DA neuron activity drive learning as a result of under- or overexpectation of reward value. We target optogenetic manipulations to different components of forced trials, when only one lever is presented, and assess lever biases on choice trials in the absence of photomanipulation. Although lever biases are demonstrated to be flexible and sensitive to changes in expected value, augmentation of cue or operant-associated DA signaling does not significantly alter choice behavior, and blunting DA signaling during any component of the forced trials reduces choice trial responses on the associated lever. These data suggest cue-evoked DA helps maintain cue-value associations but does not encode expected value as to set the benchmark against which received reward is judged.

Postpartum changes in affect-related behavior and VTA dopamine neuron activity in rats

The onset of motherhood is accompanied by alterations in emotional and affective behaviors. Many new mothers experience transient and mild depressive symptoms that typically resolve spontaneously (i.e. postpartum blues) but increase the risk for postpartum depression (PPD). There is little data regarding the neural adaptations occurring in response to parturition and shortly after birth that may be associated with these affective changes. Although the dopamine (DA) system is involved in affect, maternal motivation and PPD, little is known about postpartum DA function. We compared affective behavior in virgin and postpartum adult female rats at early and late time points. In vivo extracellular recordings of VTA DA neurons were performed to evaluate 3 parameters: number of active DA neurons (i.e. population activity), firing rate, and firing pattern. Compared with virgins, postpartum rats exhibited increased anxiety-like behavior in the elevated plus maze at 1-day postpartum; reduced social motivation at 1- and 3-days postpartum, reduced anxiety-like behavior in the novelty suppressed feeding test throughout the first week postpartum and increased forced swim test immobility at 1-day postpartum. 1- and 3-day postpartum females exhibited attenuated VTA population activity without changes in firing rate or pattern. None of these effects were observed in late postpartum females when compared with virgins. These data suggest that parturition induces time-dependent changes in a subset of affect-related behaviors and DA function during the postpartum period in rodents, with early postpartum females exhibiting depression-related phenotypes (i.e. low social motivation, higher immobility, blunted DA activity).

Region specific knockdown of Parvalbumin or Somatostatin produces neuronal and behavioral deficits consistent with those observed in schizophrenia

The anterior hippocampus and prefrontal cortex are regions linked to symptoms of schizophrenia. The anterior hippocampus is believed to be a key regulator of the mesolimbic dopamine system and is thought to be the driving force contributing to positive symptoms, while the prefrontal cortex is involved in cognitive flexibility and negative symptoms. Aberrant activity in these regions is associated with decreases in GABAergic markers, indicative of an interneuron dysfunction. Specifically, selective decreases are observed in interneurons that contain parvalbumin (PV) or somatostatin (SST). Here, we used viral knockdown in rodents to recapitulate this finding and examine the region-specific roles of PV and SST on neuronal activity and behaviors associated with positive, negative and cognitive symptoms. We found that PV and SST had differential effects on neuronal activity and behavior when knocked down in the ventral hippocampus (vHipp) or medial prefrontal cortex (mPFC). Specifically, SST or PV knockdown in the vHipp increased pyramidal cell activity of the region and produced downstream effects on dopamine neuron activity in the ventral tegmental area (VTA). In contrast, mPFC knockdown did not affect the activity of VTA dopamine neuron activity; however, it did produce deficits in negative (social interaction) and cognitive (reversal learning) domains. Taken together, decreases in PV and/or SST were sufficient to produce schizophrenia-like deficits that were dependent on the region targeted.