Abnormal functional connectivity of the reward circuit associated with early satiety in patients with postprandial distress syndrome.

Postprandial distress syndrome (PDS) is the most common functional dyspepsia (FD) subtype. Early satiety is one of the cardinal symptoms of the PDS subtype in FD patients. The heterogeneity of symptoms in FD patients hampered therapy for patients based on specific symptoms, necessitating a symptom-based understanding of the pathophysiology of FD. To investigate the correlation between reward circuit and symptom severity of PDS patients, seed (Nucleus accumbens, NAc, a key node in the reward circuit) based resting-state functional connectivity (FC) was applied in the neuroimaging data analysis. The results demonstrated that the patients with PDS manifested strengthened FC between NAc and the caudate, putamen, pallidum, amygdala, hippocampus, thalamus, anterior cingulate cortex (ACC), and insula. Moreover, the FC between NAc and ACC, insula, thalamus, and hippocampus exhibited significant positive associations with symptom severity. More importantly, the strengthened FC between NAc and the ACC, insula, amygdala, and hippocampus were found associated with the early satiety symptom of patients with PDS. This study indicated that the altered FC of reward circuit regions may play a role in the pathophysiology of patients with PDS, and some of the aberrant NAc-based FC within the reward circuit were more related to the early satiety of patients with PDS. These findings improve our symptom-based understanding of the central pathophysiology of FD, lay the groundwork for an objective diagnosis of FD, and shed light on the precise prescription for treating FD based on symptoms.

Reduced anhedonia following internet-based cognitive-behavioral therapy for depression is mediated by enhanced reward circuit activation.

BACKGROUND: Major depressive disorder (MDD) is a highly prevalent psychiatric condition, yet many patients do not receive adequate treatment. Novel and highly scalable interventions such as internet-based cognitive-behavioral-therapy (iCBT) may help to address this treatment gap. Anhedonia, a hallmark symptom of MDD that refers to diminished interest and ability to experience pleasure, has been associated with reduced reactivity in a neural reward circuit that includes medial prefrontal and striatal brain regions. Whether iCBT can reduce anhedonia severity in MDD patients, and whether these therapeutic effects are accompanied by enhanced reward circuit reactivity has yet to be examined. METHODS: Fifty-two MDD patients were randomly assigned to either 10-week iCBT (n = 26) or monitored attention control (MAC, n = 26) programs. All patients completed pre- and post-treatment assessments of anhedonia (Snaith-Hamilton Pleasure Scale; SHAPS) and reward circuit reactivity [monetary incentive delay (MID) task during functional magnetic resonance imaging (fMRI)]. Healthy control participants (n = 42) also underwent two fMRI scans while completing the MID task 10 weeks apart. RESULTS: Both iCBT and MAC groups exhibited a reduction in anhedonia severity post-treatment. Nevertheless, only the iCBT group exhibited enhanced nucleus accumbens (Nacc) and subgenual anterior cingulate cortex (sgACC) activation and functional connectivity from pre- to post-treatment in response to reward feedback. Enhanced Nacc and sgACC activations were associated with reduced anhedonia severity following iCBT treatment, with enhanced Nacc activation also mediating the reduction in anhedonia severity post-treatment. CONCLUSIONS: These findings suggest that increased reward circuit reactivity may contribute to a reduction in anhedonia severity following iCBT treatment for depression.

Obesity and Cerebral Blood Flow in the Reward Circuitry of Youth With Bipolar Disorder.

BACKGROUND: Bipolar disorder (BD) is associated with elevated body mass index (BMI) and increased rates of obesity. Obesity among individuals with BD is associated with more severe course of illness. Motivated by previous research on BD and BMI in youth as well as brain findings in the reward circuit, the current study investigates differences in cerebral blood flow (CBF) in youth BD with and without comorbid overweight/obesity (OW/OB). METHODS: Participants consisted of youth, ages 13-20 years, including BD with OW/OB (BDOW/OB; n = 25), BD with normal weight (BDNW; n = 55), and normal-weight healthy controls (HC; n = 61). High-resolution T1-weighted and pseudo-continuous arterial spin labeling images were acquired using 3 Tesla magnetic resonance imaging. CBF differences were assessed using both region of interest and whole-brain voxel-wise approaches. RESULTS: Voxel-wise analysis revealed significantly higher CBF in reward-associated regions in the BDNW group relative to the HC and BDOW/OB groups. CBF did not differ between the HC and BDOW/OB groups. There were no significant region of interest findings. CONCLUSIONS: The current study identified distinct CBF levels relating to BMI in BD in the reward circuit, which may relate to underlying differences in cerebral metabolism, compensatory effects, and/or BD severity. Future neuroimaging studies are warranted to examine for changes in the CBF-OW/OB link over time and in relation to treatment.

Neuropathological investigation of patients with prolonged anorexia nervosa.

OBJECTIVES: Recent neuroimaging studies have indicated that the mesolimbic pathway, known to work as reward neuronal circuitry, regulates cognitive-behavioral flexibility in prolonged anorexia nervosa (AN). Although AN is associated with the highest mortality rate among psychiatric disorders, there have been few neuropathological studies on this topic. This study aims to identify alterations of the reward circuitry regions, especially in the nucleus accumbens (NAcc), using AN brain tissues. METHODS: The neuronal networks in AN cases and controls were examined by immunohistochemistry directed at tyrosine hydroxylase (TH; dopaminergic neuron marker) and glial fibrillary acidic protein (GFAP; astrocyte marker). We also immunochemically analyzed frozen samples presenting astrogliosis, especially in the NAcc and striatum. RESULTS: Histologically, neuronal deformation with cytoplasmic shrinkage was seen in reward-related brain regions, such as the orbitofrontal cortex/anterior cingulate cortex. The NAcc showed massive GFAP-positive astrocytes and dot-like protrusions of astrocytes in the shell compartment. In the shell, TH and GFAP immunoreactivities revealed prominent astrogliosis within striosomes, which receive projection from the ventral tegmental area (VTA). The numbers of GFAP-positive astrocytes in the NAcc (P = 0.0079) and VTA (P = 0.0025) of AN cases were significantly higher than those of controls. Strongly immunoreactive 18 to 25 kDa bands, which might represent degradation products, were detected only in the NAcc of AN cases. Clinically, all cases presented cognitive rigidity, which might reflect a deficit of the reward pathway. CONCLUSION: Our findings suggest impaired dopaminergic innervation between the NAcc and VTA in AN. Functional dysconnectivity in the reward-related network might induce neuropsychiatric symptoms associated with AN.

Comorbidity of Post-Traumatic Stress Disorder and Alcohol Use Disorder: Animal Models and Associated Neurocircuitry.

Post-traumatic stress disorder (PTSD) and alcohol use disorder (AUD) are prevalent neuropsychiatric disorders and frequently co-occur concomitantly. Individuals suffering from this dual diagnosis often exhibit increased symptom severity and poorer treatment outcomes than those with only one of these diseases. Lacking standard preclinical models limited the exploration of neurobiological mechanisms underlying PTSD and AUD comorbidity. In this review, we summarize well-accepted preclinical model paradigms and criteria for developing successful models of comorbidity. We also outline how PTSD and AUD affect each other bidirectionally in the nervous nuclei have been heatedly discussed recently. We hope to provide potential recommendations for future research.

Circuit selectivity in drug versus natural reward seeking behaviors.

Substance use disorder (SUD) is characterized, in part by behavior biased toward drug use and away from natural sources of reward (e.g., social interaction, food, sex). The neurobiological underpinnings of SUDs reveal distinct brain regions where neuronal activity is necessary for the manifestation of SUD-characteristic behaviors. Studies that specifically examine how these regions are involved in behaviors motivated by drug versus natural reward allow determinations of which regions are necessary for regulating seeking of both reward types, and appraisals of novel SUD therapies for off-target effects on behaviors motivated by natural reward. Here, we evaluate studies directly comparing regulatory roles for specific brain regions in drug versus natural reward. While it is clear that many regions drive behaviors motivated by all reward types, based on the literature reviewed we propose a set of interconnected regions that become necessary for behaviors motivated by drug, but not natural rewards. The circuitry is selectively necessary for drug seeking includes an Action/Reward subcircuit, comprising nucleus accumbens, ventral pallidum, and ventral tegmental area, a Prefrontal subcircuit comprising prelimbic, infralimbic, and insular cortices, a Stress subcircuit comprising the central nucleus of the amygdala and the bed nucleus of the stria terminalis, and a Diencephalon circuit including lateral hypothalamus. Evidence was mixed for nucleus accumbens shell, insular cortex, and ventral pallidum. Studies for all other brain nuclei reviewed supported a necessary role in regulating both drug and natural reward seeking. Finally, we discuss emerging strategies to further disambiguate the necessity of brain regions in drug- versus natural reward-associated behaviors.

Functional specificity and neural integration in the aesthetic appreciation of artworks with implied motion.

Although there is growing interest in the neural foundations of aesthetic experience, it remains unclear how particular mental subsystems (e.g. perceptual, affective and cognitive) are involved in different types of aesthetic judgements. Here, we use fMRI to investigate the involvement of different neural networks during aesthetic judgements of visual artworks with implied motion cues. First, a behavioural experiment (N = 45) confirmed a preference for paintings with implied motion over static cues. Subsequently, in a preregistered fMRI experiment (N = 27), participants made aesthetic and motion judgements towards paintings representing human bodies in dynamic and static postures. Using functional region-of-interest and Bayesian multilevel modelling approaches, we provide no compelling evidence for unique sensitivity within or between neural systems associated with body perception, motion and affective processing during the aesthetic evaluation of paintings with implied motion. However, we show suggestive evidence that motion and body-selective systems may integrate signals via functional connections with a separate neural network in dorsal parietal cortex, which may act as a relay or integration site. Our findings clarify the roles of basic visual and affective brain circuitry in evaluating a central aesthetic feature-implied motion-while also pointing towards promising future research directions, which involve modelling aesthetic preferences as hierarchical interplay between visual and affective circuits and integration processes in frontoparietal cortex.

Childhood trauma is associated with elevated anhedonia and altered core reward circuitry in major depression patients and controls.

Childhood trauma (CT) is a well-established risk factor for major depressive disorder (MDD). However, the underlying mechanism linking CT and MDD remains not fully understood. The present study tested the hypothesis that CT have effects on specific types of anhedonia in depression via reward system. To do so, we evaluated different aspects of anhedonia and resting-state functional connectivity (FC) in reward system among 66 patients with MDD (44 with moderate-to-severe and 22 with no or low CT), and 57 healthy controls (HC; 23 with moderate-to-severe and 34 with no or low CT). Results showed that MDD patients with moderate-to-severe CT suffered more severe state anhedonic depression than patients with no or low level of CT. Individuals with moderate-to-severe CT, irrespective of MDD diagnosis, had elevated physical, social and anticipatory but not consummatory trait anhedonia, and demonstrated decreased left nucleus accumbens (NAcc)-right orbital frontal cortex (OFC) and left ventral caudate-left OFC connectivity compared to those with no or low exposure. Left NAcc-right OFC connectivity mediated relationship between CT and state anhedonia in MDD. The total altered ventral striatum (VS)-OFC connectivity mediated links between CT and physical trait anhedonia in HC. These findings highlight specific types of anhedonia and the core reward system as targets of CT. Blunted hedonic responses via decreased coupling within core reward system may be involved in the mechanism of depression following CT. Implications for clinical interventions are also discussed.

Dissection of the Drosophila neuropeptide F circuit using a high-throughput two-choice assay.

In their classic experiments, Olds and Milner showed that rats learn to lever press to receive an electric stimulus in specific brain regions. This led to the identification of mammalian reward centers. Our interest in defining the neuronal substrates of reward perception in the fruit fly Drosophila melanogaster prompted us to develop a simpler experimental approach wherein flies could implement behavior that induces self-stimulation of specific neurons in their brains. The high-throughput assay employs optogenetic activation of neurons when the fly occupies a specific area of a behavioral chamber, and the flies' preferential occupation of this area reflects their choosing to experience optogenetic stimulation. Flies in which neuropeptide F (NPF) neurons are activated display preference for the illuminated side of the chamber. We show that optogenetic activation of NPF neuron is rewarding in olfactory conditioning experiments and that the preference for NPF neuron activation is dependent on NPF signaling. Finally, we identify a small subset of NPF-expressing neurons located in the dorsomedial posterior brain that are sufficient to elicit preference in our assay. This assay provides the means for carrying out unbiased screens to map reward neurons in flies.

Brain gray matter volume of reward-related structures in Inuit adolescents pre- and postnatally exposed to lead, mercury and polychlorinated biphenyls.

This study aimed to assess associations between prenatal and postnatal exposure to lead (Pb), mercury (Hg) and polychlorinated biphenyls (PCBs) and gray matter volume of key regions of the brain reward circuit, namely the caudate nucleus, putamen, nucleus accumbens (nAcc), the amygdala, the orbitofrontal cortex (OFC) and the anterior cingulate cortex (ACC). Structural magnetic resonance imaging (MRI) was conducted in 77 Inuit adolescents (mean age = 18.39) from Nunavik, Canada, who also completed the Brief Sensation Seeking Scale (BSSS-4) and Sensation Seeking - 2 (SS-2), two self-report questionnaires evaluating the tendency toward sensation seeking, which is a proxy of reward-related behaviors. Exposures to Pb, Hg and PCBs were measured in cord blood at birth, in blood samples at 11 years old and at time of testing (18 years old). Multivariate linear regressions were corrected for multiple comparisons and adjusted for potential confounders, such as participants' sociodemographic characteristics and nutrient fish intake. Results showed that higher cord blood Pb levels predicted smaller gray matter volume in the bilateral nAcc, caudate nucleus, amygdala and OFC as well as in left ACC. A moderating effect of sex was identified, indicating that the Pb-related reduction in volume in the nAcc and caudate nucleus was more pronounced in female. Higher blood Hg levels at age 11 predicted smaller right amygdala independently of sex. No significant associations were found between blood PCBs levels at all three times of exposure. This study provides scientific support for the detrimental effects of prenatal Pb and childhood Hg blood concentrations on gray matter volume in key reward-related brain structures.

Obesity-mediated Lipoinflammation Modulates Food Reward Responses.

Accumulation of white adipose tissue (WAT) during obesity is associated with the development of chronic low-grade inflammation, a biological process known as lipoinflammation. Systemic and central lipoinflammation accumulates pro-inflammatory cytokines including IL-6, IL-1ß and TNF-α in plasma and also in brain, disrupting neurometabolism and cognitive behavior. Obesity-mediated lipoinflammation has been reported in brain regions of the mesocorticolimbic reward circuit leading to alterations in the perception and consumption of ultra-processed foods. While still under investigation, lipoinflammation targets two major outcomes of the mesocorticolimbic circuit during food reward: perception and motivation ("Wanting") and the pleasurable feeling of feeding ("Liking"). This review will provide experimental and clinical evidence supporting the contribution of obesity- or overnutrition-related lipoinflammation affecting the mesocorticolimbic reward circuit and enhancing food reward responses. We will also address neuroanatomical targets of inflammatory profiles that modulate food reward responses during obesity and describe potential cellular and molecular mechanisms of overnutrition linked to addiction-like behavior favored by brain lipoinflammation.

Distinguishing between bipolar depression and unipolar depression based on the reward circuit activities and clinical characteristics: A machine learning analysis.

BACKGROUND: Differentiating bipolar depression (BD) from unipolar depression (UD) is a major clinical challenge. Identifying the potential classifying biomarkers between these two diseases is vital to optimize personalized management of depressed individuals. METHODS: Here, we aimed to integrate neuroimaging and clinical data with machine learning method to classify BD and UD at the individual level. Data were collected from 31 healthy controls (HC group) and 80 depressive patients with an average follow-up period of 7.51 years. Of these patients, 32 got diagnosis conversion from major depressive disorder (MDD) to BD (BD group) and 48 remain persistent diagnosis of MDD (MDD group). Using graph theory and functional connectivity (FC) analysis, we investigated the differences in reward circuit properties among three groups. Then we applied a support vector machine and leave-one-out cross-validation methods to classify BD and UD patients based on neuroimaging and clinical data. RESULTS: Compared with MDD and HC, BD showed decreased degree centrality of right mediodorsal thalamus (MD) and nodal efficiency (NE) of left ventral pallidum. Compared with BD and HC, MDD showed decreased NE of right MD and increased FC between right MD and bilateral dorsolateral prefrontal cortex and left ventromedial prefrontal cortex. Notably, the classifier obtained high classification accuracies (87.50 %) distinguishing BD and UD patients based on reward circuit properties and clinical features. LIMITATIONS: The classifying model requires out-of-sample replication analysis. CONCLUSION: The reward circuit dysfunction can not only provide additional information to assist clinical differential diagnosis, but also in turn informed treatment decision of depressive patients.

A review on the role of metabotropic glutamate receptors in neuroplasticity following psychostimulant use disorder.

Psychostimulant Use Disorder (PUD) is a chronic relapsing disorder with high motivation for drug abuse. In addition to developing PUD, the use of psychostimulants is a growing public health concern because it is associated with several physical and mental health impairments. To date, there are no FDA-confirmed medicines for the treatment of psychostimulant abuse; therefore, clarification of the cellular and molecular alterations participating in PUD is crucial for developing beneficial medications. PUD causes extensive neuroadaptations in glutamatergic circuitry involved in reinforcement and reward processing. These adaptations include both transient and long-lasting changes in glutamate transmission and glutamate receptors, especially metabotropic glutamate receptors, that have been linked to developing and maintaining PUD. Here, we review the roles of all groups of mGluRs,including I,II, and III in synaptic plasticity within brain reward circuitry engaged by psychostimulants (cocaine, amphetamine, methamphetamine, and nicotine). The review concentrates on investigations of psychostimulant-induced behavioral and neurological plasticity, with an ultimate goal to explore circuit and molecular targets with the potential to contribute to the treatment of PUD.

Genetic Tagging Uncovers a Robust, Selective Activation of the Thalamic Paraventricular Nucleus by Adverse Experiences Early in Life.

Background: Early-life adversity (ELA) is associated with increased risk for mood disorders, including depression and substance use disorders. These disorders are characterized by impaired reward-related behaviors, suggesting compromised operations of reward-related brain circuits. However, the brain regions engaged by ELA that mediate these enduring consequences of ELA remain largely unknown. In an animal model of ELA, we identified aberrant reward-seeking behaviors, a discovery that provides a framework for assessing the underlying circuits. Methods: Employing TRAP2 (targeted recombination in active populations) male and female mice, in which neurons activated within a defined time frame are permanently tagged, we compared ELA- and control-reared mice, assessing the quantity and distribution of ELA-related neuronal activation. After validating the TRAP2 results using native c-Fos labeling, we defined the molecular identity of this population of activated neurons. Results: We uniquely demonstrated that the TRAP2 system is feasible and efficacious in neonatal mice. Surprisingly, the paraventricular nucleus of the thalamus was robustly and almost exclusively activated by ELA and was the only region distinguishing ELA from typical rearing. Remarkably, a large proportion of ELA-activated paraventricular nucleus of the thalamus neurons expressed CRF1, the receptor for the stress-related peptide, corticotropin-releasing hormone, but these neurons did not express corticotropin-releasing hormone itself. Conclusions: The paraventricular nucleus of the thalamus, an important component of reward circuits that is known to encode remote, emotionally salient experiences to influence future motivated behaviors, encodes adverse experiences as remote as those occurring during the early postnatal period and is thus poised to contribute to the enduring deficits in reward-related behaviors consequent to ELA.

Functional connectivity alterations in reward-related circuits associated with non-suicidal self-injury behaviors in drug-naïve adolescents with depression.

Non-suicidal self-injury (NSSI) behaviors are a major public health concern among adolescents with depression. Such behaviors may be associated with the reward system. However, the underlying mechanism in patients with depression and NSSI still remains unclear. A total of 56 drug-naïve adolescents with depression, including 23 patients with NSSI (the NSSI group) and 33 patients without NSSI (the nNSSI group), and 25 healthy controls (HCs) were recruited in this study. Seed-based functional connectivity (FC) was used to explore the NSSI-related FC alterations in the reward circuit. Correlation analysis was conducted between the altered FCs and clinical data. Compared with the nNSSI group, the NSSI group showed greater FC between left nucleus accumbens (NAcc) and right lingual gyrus and between right putamen accumbens and right angular gyrus (ANG). The NSSI group also had declined FC between right NAcc and left inferior cerebellum, between left cingulate gyrus (CG) and right ANG, between left CG and left middle temporal gyrus (MTG), and between right CG and bilateral MTG (voxel-wise p < 0.01, cluster-wise p < 0.05, Gaussian random field correction). The FC between right NAcc and left inferior cerebellum was found positively correlated with the score of addictive features of NSSI (r = 0.427, p = 0.042). Our findings indicated that the regions in the reward circuit with NSSI-related FC alterations included bilateral NAcc, right putamen and bilateral CG, which may provide new evidence on the neural mechanisms of NSSI behaviors in adolescents with depression.

The Periaqueductal Gray and Its Extended Participation in Drug Addiction Phenomena.

The periaqueductal gray (PAG) is a complex mesencephalic structure involved in the integration and execution of active and passive self-protective behaviors against imminent threats, such as immobility or flight from a predator. PAG activity is also associated with the integration of responses against physical discomfort (e.g., anxiety, fear, pain, and disgust) which occurs prior an imminent attack, but also during withdrawal from drugs such as morphine and cocaine. The PAG sends and receives projections to and from other well-documented nuclei linked to the phenomenon of drug addiction including: (i) the ventral tegmental area; (ii) extended amygdala; (iii) medial prefrontal cortex; (iv) pontine nucleus; (v) bed nucleus of the stria terminalis; and (vi) hypothalamus. Preclinical models have suggested that the PAG contributes to the modulation of anxiety, fear, and nociception (all of which may produce physical discomfort) linked with chronic exposure to drugs of abuse. Withdrawal produced by the major pharmacological classes of drugs of abuse is mediated through actions that include participation of the PAG. In support of this, there is evidence of functional, pharmacological, molecular. And/or genetic alterations in the PAG during the impulsive/compulsive intake or withdrawal from a drug. Due to its small size, it is difficult to assess the anatomical participation of the PAG when using classical neuroimaging techniques, so its physiopathology in drug addiction has been underestimated and poorly documented. In this theoretical review, we discuss the involvement of the PAG in drug addiction mainly via its role as an integrator of responses to the physical discomfort associated with drug withdrawal.

Understanding the genetics and neurobiological pathways behind addiction (Review).

The hypothesis issued by modern medicine states that many diseases known to humans are genetically determined, influenced or not by environmental factors, which is applicable to most psychiatric disorders as well. This article focuses on two pending questions regarding addiction: Why do some individuals become addicted while others do not? along with Is it a learned behavior or is it genetically predefined? Recent data suggest that addiction is more than repeated exposure, it is the synchronicity between intrinsic factors (genotype, sex, age, preexisting addictive disorder, or other mental illness), extrinsic factors (childhood, level of education, socioeconomic status, social support, entourage, drug availability) and the nature of the addictive agent (pharmacokinetics, path of administration, psychoactive properties). The dopamine-mesolimbic motivation-reward-reinforcement cycle remains the most coherent physiological theory in addiction. While the common property of addictive substances is that they are dopamine-agonists, each class has individual mechanisms, pharmacokinetics and psychoactive potentials.

Sex-specific static and dynamic functional networks of sub-divisions of striatum linking to the greed personality trait.

The study of greed has been broadly investigated and discussed in the field of social sciences, including economics, political science, and psychology. However, the neural mechanisms underlying greed personality trait (GPT) have received little attention from the cognitive neuroscience field and still remain unclear. In this study, we explored the associations between GPT and static/dynamic reward circuit-specifically its sub-regions' functional networks including caudate, nucleus accumbens (NAcc), and putamen. Behavioral analyses revealed significant associations of GPT with Past-Negative and Present-Fatalistic time attitude as well as attention impulsivity. Imaging analyses revealed a significant interaction effect between sex and GPT on the static reward functional networks. In particular, GPT was positively correlated with static caudate-NAcc, caudate-cerebellum, and NAcc-parahippocampus/medial orbitofrontal cortex (PHG/mOFC) for males but negatively correlated for females. GPT was also marginally and negatively correlated with static putamen-occipital pole functional connectivities among males. Interestingly, sex difference interaction patterns were further observed in the dynamic reward functional networks. Further, dynamic reward functional networks also exhibited some specific characteristics, manifesting in more brain regions involved for greedy behaviors. These findings suggest sex-specific static and dynamic functional networks underlying human dispositional greed, and also implicate the critical contributions of reward circuit, especially for sub-circuits of reward, on greed.

Retinal dysfunctions in regular tobacco users: The retina as a window to the reward circuit in addictive disorders.

The nicotine contained in tobacco is a neuromodulator which affects neurotransmission within the brain. The retina is an easy way to study central synaptic transmission dysfunctions in neuropsychiatric disorders. The purpose of this study is to assess the impact of regular tobacco use on retinal function using pattern (PERG), flash (fERG) and multifocal (mfERG) electroretinogram (ERG). We recorded PERG, fERG and mfERG for 24 regular tobacco users and 30 healthy non-smoking subjects. The protocol was compliant with International Society for Clinical Electrophysiology of Vision standards. The amplitudes and peak times (PT) of P50, N95 waves (PERG), a-, b- and oscillatory potentials (fERG), and N1, P1, N2 (mfERG) were evaluated. Compared to non-smokers, the results (Mann-Whitney U test, Bonferroni correction) for tobacco users suggested a significant increase of ~ 1 ms in the PT of light-adapted 3.0 fERG b-wave (p = 0.002). Using mfERG, we observed the following increases in tobacco users: in ring 3 for P1 PT of ~1,5 ms and in ring 5 for P1 PT of ~ 1 ms and for N2 PT of ~ 1 ms (p = 0.002, p = 0.002 and p = 0.006). It is our hypothesis that these results reflect the consequences of regular tobacco use on retinal synaptic transmission, and more specifically on dopaminergic and cholinergic transmission. We deduce that the retina may provide a crucial site of investigation for neurotransmission modulation of the reward circuit in regular tobacco users.

Drug-activated cells: From immediate early genes to neuronal ensembles in addiction.

Beyond their rapid rewarding effects, drugs of abuse can durably alter an individual's response to their environment as illustrated by the compulsive drug seeking and risk of relapse triggered by drug-associated stimuli. The persistence of these associations even long after cessation of drug use demonstrates the enduring mark left by drugs on brain reward circuits. However, within these circuits, neuronal populations are differently affected by drug exposure and growing evidence indicates that relatively small subsets of neurons might be involved in the encoding and expression of drug-mediated associations. The identification of sparse neuronal populations recruited in response to drug exposure has benefited greatly from the study of immediate early genes (IEGs) whose induction is critical in initiating plasticity programs in recently activated neurons. In particular, the development of technologies to manipulate IEG-expressing cells has been fundamental to implicate broadly distributed neuronal ensembles coincidently activated by either drugs or drug-associated stimuli and to then causally establish their involvement in drug responses. In this review, we summarize the literature regarding IEG regulation in different learning paradigms and addiction models to highlight their role as a marker of activity and plasticity. As the exploration of neuronal ensembles in addiction improves our understanding of drug-associated memory encoding, it also raises several questions regarding the cellular and molecular characteristics of these discrete neuronal populations as they become incorporated in drug-associated neuronal ensembles. We review recent efforts towards this goal and discuss how they will offer a more comprehensive understanding of addiction pathophysiology.