Effect of MCH1, a fatty-acid amide hydrolase inhibitor, on the depressive-like behavior and gene expression of endocannabinoid and dopaminergic-signaling system in the mouse nucleus accumbens

Abstract MCH1 is a synthetic macamide that has shown in vitro inhibitory activity on fatty acid amide hydrolase (FAAH), an enzyme responsible for endocannabinoid metabolism. This inhibition can modulate endocannabinoid and dopamine signaling in the nucleus accumbens (NAc), potentially having an antidepressant-like effect. The present study aimed to evaluate the effect of the in vivo administration of MCH1 (3, 10, and 30 mg/kg, ip) in 2-month-old BALB/c male mice (n=97) on forced swimming test (FST), light-dark box (LDB), and open field test (OFT) and on early gene expression changes 2 h after drug injection related to the endocannabinoid system (Cnr1 and Faah) and dopaminergic signaling (Drd1 and Drd2) in the NAc core. We found that the 10 mg/kg MCH1 dose reduced the immobility time compared to the vehicle group in the FST with no effect on anxiety-like behaviors measured in the LDB or OFT. However, a 10 mg/kg MCH1 dose increased locomotor activity in the OFT compared to the vehicle. Moreover, RT-qPCR results showed that the 30 mg/kg MCH1 dose increased Faah gene expression by 2.8-fold, and 10 mg/kg MCH1 increased the Cnr1 gene expression by 4.3-fold compared to the vehicle. No changes were observed in the expression of the Drd1 and Drd2 genes in the NAc at either MCH1 dose. These results indicated that MCH1 might have an antidepressant-like effect without an anxiogenic effect and induces significant changes in endocannabinoid-related genes but not in genes of the dopaminergic signaling system in the NAc of mice.

Methcathinone Increases Visually-evoked Neuronal Activity and Enhances Sensory Processing Efficiency in Mice / 神经科学通报·英文版

Methcathinone (MCAT) belongs to the designer drugs called synthetic cathinones, which are abused worldwide for recreational purposes. It has strong stimulant effects, including enhanced euphoria, sensation, alertness, and empathy. However, little is known about how MCAT modulates neuronal activity in vivo. Here, we evaluated the effect of MCAT on neuronal activity with a series of functional approaches. C-Fos immunostaining showed that MCAT increased the number of activated neurons by 6-fold, especially in sensory and motor cortices, striatum, and midbrain motor nuclei. In vivo single-unit recording and two-photon Ca2+ imaging revealed that a large proportion of neurons increased spiking activity upon MCAT administration. Notably, MCAT induced a strong de-correlation of population activity and increased trial-to-trial reliability, specifically during a natural movie stimulus. It improved the information-processing efficiency by enhancing the single-neuron coding capacity, suggesting a cortical network mechanism of the enhanced perception produced by psychoactive stimulants.

Probabilistic Tractography Between Nucleus Accumbens and Other Reward-related Brain Areas in Malay Female Adolescents

@#Introduction: Studies show that adolescents are more reward sensitive compared to other age groups. The nucleus accumbens (NAcc) has been identified as a key brain area involved in reward through its connectivity to other reward-related brain areas. Our study aimed to characterise the white matter structural connectivity of nucleus accumbens with brain areas that are most often associated with reward in female adolescents. Methods: Fifteen healthy female Malay adolescents were recruited and underwent diffusion-weighted brain scanning. Two behaviour scales were also given to verify typical reward responsiveness. Then, probabilistic tractography and NAcc segmentation were performed on the data using FMRIB Software Library (FSL). Probabilistic tractography was performed to determine the relative connection probability of nucleus accumbens (NAcc) to areas shown to be associated with reward, namely amygdala, anterior cingulate cortex (ACC), medial orbitofrontal cortex (mOFC), hippocampus, ventrolateral prefrontal cortex (vlPFC) and dorsolateral prefrontal cortex (dlPFC). Connectivity-based segmentation of NAcc was performed to determine the spatial distribution of its connectivity with the target brain areas according to the highest connection probability. Results: The highest relative connection probability was found between NAcc to mOFC, while the NAcc parcellation showed the widest distribution of connection to mOFC compared to the other five targets on both sides of the brain. Conclusion: Our findings demonstrated the strongest structural connectivity and widest distribution between NAcc and mOFC compared with other brain areas related to reward. This study’s findings could be used as baseline to compare with people with atypical reward circuit problems.

Role of circTmeff-1 in morphine addiction memory of mice / 中国药理学与毒理学杂志

In addition to the essential pharmacologi-cal effects of opioids,situational cues associated with drug addiction memory are key triggers for drug seeking.CircRNAs,an emerging hotspot regulator in crown genet-ics-play an important role in central nervous system-relat-ed diseases.However,the internal mediating mechanism of circRNA in the field of drug reward and addiction mem-ory remains unknown.Here,we trained mice on a condi-tional place preference(CPP)model and collected nucle-us accumbens(NAc)tissues from day 1(T0)and day 8(T1)for high-throughput RNA sequencing.qRT-PCR revealed that circTmeff-1 was highly expressed in the NAc core but not in the NAc shell,suggesting that it plays a role in addiction memory formation.Meanwhile,the reverse regulation of circTmeff-1 by adeno-associated viruses could both inhibit the formation of addiction mem-ory in the NAc core or shell.Subsequently,the GO and KEGG analyses indicated 21 that circTmeff-1 might regu-late the addiction memory via the MAPK and AMPK path-ways.These findings suggest that circTmeff-1 in NAc plays a crucial role in morphine-dependent memory for-mation.

The Nucleus Accumbens CRH-CRHR1 System Mediates Early-Life Stress-Induced Sleep Disturbance and Dendritic Atrophy in the Adult Mouse / 神经科学通报·英文版

Adverse experiences in early life have long-lasting negative impacts on behavior and the brain in adulthood, one of which is sleep disturbance. As the corticotropin-releasing hormone (CRH)-corticotropin-releasing hormone receptor 1 (CRHR1) system and nucleus accumbens (NAc) play important roles in both stress responses and sleep-wake regulation, in this study we investigated whether the NAc CRH-CRHR1 system mediates early-life stress-induced abnormalities in sleep-wake behavior in adult mice. Using the limited nesting and bedding material paradigm from postnatal days 2 to 9, we found that early-life stress disrupted sleep-wake behaviors during adulthood, including increased wakefulness and decreased non-rapid eye movement (NREM) sleep time during the dark period and increased rapid eye movement (REM) sleep time during the light period. The stress-induced sleep disturbances were accompanied by dendritic atrophy in the NAc and both were largely reversed by daily systemic administration of the CRHR1 antagonist antalarmin during stress exposure. Importantly, Crh overexpression in the NAc reproduced the effects of early-life stress on sleep-wake behavior and NAc morphology, whereas NAc Crhr1 knockdown reversed these effects (including increased wakefulness and reduced NREM sleep in the dark period and NAc dendritic atrophy). Together, our findings demonstrate the negative influence of early-life stress on sleep architecture and the structural plasticity of the NAc, and highlight the critical role of the NAc CRH-CRHR1 system in modulating these negative outcomes evoked by early-life stress.

Perinatal exposure to a high-fat diet alters proopiomelanocortin, neuropeptide Y and dopaminergic receptors gene expression and the food preference in offspring adult rats / Exposição perinatal a uma dieta hiperlipídica altera a expressão gênica de proopiomelanocortina, neuropepitídeo Y e receptores dopaminérgicos e a preferência alimentar em ratos adultos descendentes

Exposure to the hight-fat diet may alter the control of food intake promoting hyperphagia and obesity. The objective of this study was to investigate the effects of this diet on dopamine receptors (drd1 and drd2), proopiomelanocortin (pomc), neuropeptideY (npy) genes expression, and preference food in adult rats. Wistar female rats were fed a hight-fat or control diet during pregnancy and lactation. The offspring were allocated into groups: Lactation - Control (C) and High-fat (H). Post-weaning ­ Control Control (CC), offspring of mothers C, fed a control diet after weaning; Control Hight-fat (CH), offspring of mothers C, fed a hight-fat diet after weaning; Hight-fat Control (HC), offspring of mothers H, fed with control diet after weaning; and Hight-fat Hight-fat (HH), offspring of mothers H, fed a H diet after weaning. The groups CH and HH presented greater expression of drd1 in comparison to the CC. The drd2 of CH and HC presented higher gene expression than did CC. HH presented higher pomc expression in comparison to the other groups. HC also presented greater expression in comparison to CH. The npy of HH presented greater expression in relation to CH and HC. HH and HC have had a higher preference for a high-fat diet at 102º life's day. The high-fat diet altered the gene expression of the drd1, drd2, pomc and npy, and influencing the food preference for high-fat diet.

A exposição à dieta hiperlipídica pode alterar o controle da ingestão de alimentos, promovendo hiperfagia e obesidade. O objetivo deste estudo foi investigar os efeitos dessa dieta sobre a expressão gênica dos receptores de dopamina (drd1 e drd2), da proopiomelanocortina (pomc) e neuropeptídeo Y (npy), e preferência alimentar em ratos adultos. Ratas Wistar foram alimentadas com uma dieta hiperlipídica ou controle durante a gestação e lactação. Os descendentes foram alocados em grupos: Lactação ­ Controle (C) e Hiperlipídica (H). Pós-desmame - Controle Controle (CC), descendentes das genitoras do grupo controle e alimentados com dieta controle após o desmame; Controle Hiperlipídica (CH), descendentes das genitoras do grupo controle e alimentados com dieta hiperlipídica após o desmame; Hiperlipídica Controle (HC), descendentes das genitoras do grupo hiperlipídica e alimentados com dieta controle após o desmame; Hiperlipídica Hiperlipídica (HH), descendentes das genitoras do grupo hiperlipídica e alimentados com dieta hiperlipídica após o desmame. Os grupos CH e HH apresentaram maior expressão de drd1 em comparação ao CC. O drd2 de CH e HC apresentou maior expressão gênica que o CC. HH apresentou maior expressão de pomc em comparação com os outros grupos. O HC também apresentou maior expressão de pomc em comparação ao CH. O npy do HH apresentou maior expressão em relação ao CH e HC. HH e HC tiveram uma preferência maior por uma dieta rica em gordura no 102º dia de vida. A dieta hiperlipídica alterou a expressão gênica dos drd1, drd2, pomc e npy e influenciou na preferência alimentar pela dieta hiperlipídica.

Perinatal exposure to a high-fat diet alters proopiomelanocortin, neuropeptide Y and dopaminergic receptors gene expression and the food preference in offspring adult rats / Exposição perinatal a uma dieta hiperlipídica altera a expressão gênica de proopiomelanocortina, neuropepitídeo Y e receptores dopaminérgicos e a preferência alimentar em ratos adultos descendentes

Exposure to the hight-fat diet may alter the control of food intake promoting hyperphagia and obesity. The objective of this study was to investigate the effects of this diet on dopamine receptors (drd1 and drd2), proopiomelanocortin (pomc), neuropeptideY (npy) genes expression, and preference food in adult rats. Wistar female rats were fed a hight-fat or control diet during pregnancy and lactation. The offspring were allocated into groups: Lactation – Control (C) and High-fat (H). Post- weaning – Control Control (CC), offspring of mothers C, fed a control diet after weaning; Control Hight-fat (CH), offspring of mothers C, fed a hight-fat diet after weaning; Hight-fat Control (HC), offspring of mothers H, fed with control diet after weaning; and Hight-fat Hight-fat (HH), offspring of mothers H, fed a H diet after weaning. The groups CH and HH presented greater expression of drd1 in comparison to the CC. The drd2 of CH and HC presented higher gene expression than did CC. HH presented higher pomc expression in comparison to the other groups. HC also presented greater expression in comparison to CH. The npy of HH presented greater expression in relation to CH and HC. HH and HC have had a higher preference for a high-fat diet at 102º life’s day. The high-fat diet altered the gene expression of the drd1, drd2, pomc and npy, and influencing the food preference for high-fat diet.

A exposição à dieta hiperlipídica pode alterar o controle da ingestão de alimentos, promovendo hiperfagia e obesidade. O objetivo deste estudo foi investigar os efeitos dessa dieta sobre a expressão gênica dos receptores de dopamina (drd1 e drd2), da proopiomelanocortina (pomc) e neuropeptídeo Y (npy), e preferência alimentar em ratos adultos. Ratas Wistar foram alimentadas com uma dieta hiperlipídica ou controle durante a gestação e lactação. Os descendentes foram alocados em grupos: Lactação – Controle (C) e Hiperlipídica (H). Pós-desmame – Controle Controle (CC), descendentes das genitoras do grupo controle e alimentados com dieta controle após o desmame; Controle Hiperlipídica (CH), descendentes das genitoras do grupo controle e alimentados com dieta hiperlipídica após o desmame; Hiperlipídica Controle (HC), descendentes das genitoras do grupo hiperlipídica e alimentados com dieta controle após o desmame; Hiperlipídica Hiperlipídica (HH), descendentes das genitoras do grupo hiperlipídica e alimentados com dieta hiperlipídica após o desmame. Os grupos CH e HH apresentaram maior expressão de drd1 em comparação ao CC. O drd2 de CH e HC apresentou maior expressão gênica que o CC. HH apresentou maior expressão de pomc em comparação com os outros grupos. O HC também apresentou maior expressão de pomc em comparação ao CH. O npy do HH apresentou maior expressão em relação ao CH e HC. HH e HC tiveram uma preferência maior por uma dieta rica em gordura no 102º dia de vida. A dieta hiperlipídica alterou a expressão gênica dos drd1, drd2, pomc e npy e influenciou na preferência alimentar pela dieta hiperlipídica.

Perinatal exposure to a high-fat diet alters proopiomelanocortin, neuropeptide Y and dopaminergic receptors gene expression and the food preference in offspring adult rats

Abstract Exposure to the hight-fat diet may alter the control of food intake promoting hyperphagia and obesity. The objective of this study was to investigate the effects of this diet on dopamine receptors (drd1 and drd2), proopiomelanocortin (pomc), neuropeptideY (npy) genes expression, and preference food in adult rats. Wistar female rats were fed a hight-fat or control diet during pregnancy and lactation. The offspring were allocated into groups: Lactation Control (C) and High-fat (H). Post-weaning Control Control (CC), offspring of mothers C, fed a control diet after weaning; Control Hight-fat (CH), offspring of mothers C, fed a hight-fat diet after weaning; Hight-fat Control (HC), offspring of mothers H, fed with control diet after weaning; and Hight-fat Hight-fat (HH), offspring of mothers H, fed a H diet after weaning. The groups CH and HH presented greater expression of drd1 in comparison to the CC. The drd2 of CH and HC presented higher gene expression than did CC. HH presented higher pomc expression in comparison to the other groups. HC also presented greater expression in comparison to CH. The npy of HH presented greater expression in relation to CH and HC. HH and HC have had a higher preference for a high-fat diet at 102º lifes day. The high-fat diet altered the gene expression of the drd1, drd2, pomc and npy, and influencing the food preference for high-fat diet.

Resumo A exposição à dieta hiperlipídica pode alterar o controle da ingestão de alimentos, promovendo hiperfagia e obesidade. O objetivo deste estudo foi investigar os efeitos dessa dieta sobre a expressão gênica dos receptores de dopamina (drd1 e drd2), da proopiomelanocortina (pomc) e neuropeptídeo Y (npy), e preferência alimentar em ratos adultos. Ratas Wistar foram alimentadas com uma dieta hiperlipídica ou controle durante a gestação e lactação. Os descendentes foram alocados em grupos: Lactação Controle (C) e Hiperlipídica (H). Pós-desmame Controle Controle (CC), descendentes das genitoras do grupo controle e alimentados com dieta controle após o desmame; Controle Hiperlipídica (CH), descendentes das genitoras do grupo controle e alimentados com dieta hiperlipídica após o desmame; Hiperlipídica Controle (HC), descendentes das genitoras do grupo hiperlipídica e alimentados com dieta controle após o desmame; Hiperlipídica Hiperlipídica (HH), descendentes das genitoras do grupo hiperlipídica e alimentados com dieta hiperlipídica após o desmame. Os grupos CH e HH apresentaram maior expressão de drd1 em comparação ao CC. O drd2 de CH e HC apresentou maior expressão gênica que o CC. HH apresentou maior expressão de pomc em comparação com os outros grupos. O HC também apresentou maior expressão de pomc em comparação ao CH. O npy do HH apresentou maior expressão em relação ao CH e HC. HH e HC tiveram uma preferência maior por uma dieta rica em gordura no 102º dia de vida. A dieta hiperlipídica alterou a expressão gênica dos drd1, drd2, pomc e npy e influenciou na preferência alimentar pela dieta hiperlipídica.

Effects of nucleus accumbens GABA-lateral hypothalamic area MCH neural pathway on rewarding feeding / 中华行为医学与脑科学杂志

Objective:To explore the effects of the γ-aminobutyric acid(GABA) neurons and melanin-concentrating hormone (MCH) neurons of the nucleus accumbens (NAc)-lateral hypothalamic area (LHA) neural pathway on the rewarding feeding(palatable food sweat condensed milk) in the obesity rats.Methods:Total 142 male Wistar rats of SPF grade were divided into normal diet (ND) group ( n=68) and high-fat diet induced obesity (DIO) group ( n=74) according to the principle of body mass matching. The rats in the two groups were given normal diet and high-fat diet for 8 weeks. Eight weeks later, 6 DIO rats were randomly selected to observe the nerve projection from GABA neurons in NAc to MCH neurons in LHA by fluorogold retrograde tracing combined fluorescence immunohistochemistry. And the expressions of c-Fos and MCH in LHA after ingestion of sweet condensed milk(rewarding feeding) were observed by fluorescence immunohistochemistry (6 rats in each group). GABA receptor agonist Musimol or GABA receptor antagonist Bicuculine was microinjected into the nucleus of LHA to observe the effect of GABA on rewarding food intake in ND and DIO rats ( n=8 in each group), and the changes of rewarding food intake after blocking MCH signal ( n=8 in each group). SPSS 17.0 was used for statistical analysis, two-way ANOVA and post hoc Bonferroni test were used for comparison among multiple groups, and t-test was used for comparison between two groups. Results:After 8 weeks of high-fat diet modeling, the intake of delicious food in DIO rats was significantly higher than that in ND rats((12.52±2.29) mL, (7.45±1.23) mL, t=4.778, P<0.01) after satiety.The results of fluorogold retrograde tracing combined with fluorescence immunohistochemistry showed that GABA neurons in NAc projected nerve fibers to neurons in LHA, and GABA A receptors in some neurons in LHA coexisted with MCH.The results of NAc-LHA pathway on delicious food intake showed that the interaction between rat group and drug intervention was significant( F=9.869, P<0.01). Simple effect analysis showed that the intake of delicious food after microinjection of Musimol into LHA nucleus of ND rats was significantly lower than that of microinjection normal saline ((4.25±1.38) mL, (7.29±1.49) mL, P<0.01), while the intake of delicious food after injection of Bicuculine was significantly higher than that of microinjection normal saline((10.72±2.11) mL, (7.29±1.49) mL, P<0.05). The intake of delicious food after microinjection of Musimol into LHA nucleus in DIO group was significantly lower than that of microinjection normal saline((3.51±1.77)mL, (13.68±2.95) mL, P<0.01), but there was no significant difference between microinjection Bicuculine and microinjection normal saline ((14.83±3.44) mL, (13.68±2.95) mL, P>0.05). The results of blocking MCH signal on delicious food intake showed that the interaction effect between SNAP-94847 and Bicuculine intervention was not significant ( F=1.468, P>0.05). The main effect of SNAP-94847 intervention was significant ( F=15.880, P<0.01)and the main effect of Bicuculine intervention was significant ( F=6.930, P<0.05). After intracerebroventricular injection of MCH receptor blocker SNAP-94847, the delicious food intake of ND rats was significantly less than that of injection normal saline((4.78±1.72) mL, (7.63±2.77) mL, P<0.05), and it was not affected by pre injection of Bicuculine in LHA ((6.24±2.18) mL, (4.78±1.72) mL, P>0.05). In the DIO rats, the interaction effect between SNAP-94847 and Bicuculine intervention was not significant( F=0.006, P>0.05). The main effect of SNAP-94847 intervention was significant ( F=18.46, P<0.01) and the main effect of Bicuculine intervention was not significant ( F=2.059, P>0.05). After intracerebroventricular injection of MCH receptor blocker SNAP-94847, the delicious food intake of DIO rats was significantly lower than that of injection normal saline((6.89±2.11) mL, (12.19±4.36) mL, P<0.05), and it was not affected by pre injection of Bicuculine in LHA ((8.72±2.26) mL, (6.89±2.11) mL, P>0.05). Conclusion:GABAergic signal in NAc can regulate the expression of MCH in neurons of LHA. In the DIO rats, the sensitivity of MCH neurons in LHA to satiety signal decreases and the hedonic feeding increases.

Projections from D2 Neurons in Different Subregions of Nucleus Accumbens Shell to Ventral Pallidum Play Distinct Roles in Reward and Aversion / 神经科学通报·英文版

The nucleus accumbens shell (NAcSh) plays an important role in reward and aversion. Traditionally, NAc dopamine receptor 2-expressing (D2) neurons are assumed to function in aversion. However, this has been challenged by recent reports which attribute positive motivational roles to D2 neurons. Using optogenetics and multiple behavioral tasks, we found that activation of D2 neurons in the dorsomedial NAcSh drives preference and increases the motivation for rewards, whereas activation of ventral NAcSh D2 neurons induces aversion. Stimulation of D2 neurons in the ventromedial NAcSh increases movement speed and stimulation of D2 neurons in the ventrolateral NAcSh decreases movement speed. Combining retrograde tracing and in situ hybridization, we demonstrated that glutamatergic and GABAergic neurons in the ventral pallidum receive inputs differentially from the dorsomedial and ventral NAcSh. All together, these findings shed light on the controversy regarding the function of NAcSh D2 neurons, and provide new insights into understanding the heterogeneity of the NAcSh.

CCL2/CCR2 Contributes to the Altered Excitatory-inhibitory Synaptic Balance in the Nucleus Accumbens Shell Following Peripheral Nerve Injury-induced Neuropathic Pain / 神经科学通报·英文版

The medium spiny neurons (MSNs) in the nucleus accumbens (NAc) integrate excitatory and inhibitory synaptic inputs and gate motivational and emotional behavior output. Here we report that the relative intensity of excitatory and inhibitory synaptic inputs to MSNs of the NAc shell was decreased in mice with neuropathic pain induced by spinal nerve ligation (SNL). SNL increased the frequency, but not the amplitude of spontaneous inhibitory postsynaptic currents (sIPSCs), and decreased both the frequency and amplitude of spontaneous excitatory postsynaptic currents (sEPSCs) in the MSNs. SNL also decreased the paired-pulse ratio (PPR) of evoked IPSCs but increased the PPR of evoked EPSCs. Moreover, acute bath application of C–C motif chemokine ligand 2 (CCL2) increased the frequency and amplitude of sIPSCs and sEPSCs in the MSNs, and especially strengthened the amplitude of N-methyl-D-aspartate receptor (NMDAR)-mediated miniature EPSCs. Further Ccl2 overexpression in the NAc in vivo decreased the peak amplitude of the sEPSC/sIPSC ratio. Finally, Ccr2 knock-down improved the impaired induction of NMDAR-dependent long-term depression (LTD) in the NAc after SNL. These results suggest that CCL2/CCR2 signaling plays a role in the integration of excitatory/inhibitory synaptic transmission and leads to an increase of the LTD induction threshold at the synapses of MSNs during neuropathic pain.

Reduced Firing of Nucleus Accumbens Parvalbumin Interneurons Impairs Risk Avoidance in DISC1 Transgenic Mice / 神经科学通报·英文版

A strong animal survival instinct is to approach objects and situations that are of benefit and to avoid risk. In humans, a large proportion of mental disorders are accompanied by impairments in risk avoidance. One of the most important genes involved in mental disorders is disrupted-in-schizophrenia-1 (DISC1), and animal models in which this gene has some level of dysfunction show emotion-related impairments. However, it is not known whether DISC1 mouse models have an impairment in avoiding potential risks. In the present study, we used DISC1-N terminal truncation (DISC1-N

Reduced Firing of Nucleus Accumbens Parvalbumin Interneurons Impairs Risk Avoidance in DISC1 Transgenic Mice / 神经科学通报·英文版

A strong animal survival instinct is to approach objects and situations that are of benefit and to avoid risk. In humans, a large proportion of mental disorders are accompanied by impairments in risk avoidance. One of the most important genes involved in mental disorders is disrupted-in-schizophrenia-1 (DISC1), and animal models in which this gene has some level of dysfunction show emotion-related impairments. However, it is not known whether DISC1 mouse models have an impairment in avoiding potential risks. In the present study, we used DISC1-N terminal truncation (DISC1-N

Estimulación cerebral profunda en el núcleo accumbens en pacientes con depresión resistente al tratamiento: reporte de casos / Nucleus accumbens deep brain stimulation in patients with treatment-resistant depression: report of four cases

INTRODUCCIÓN: La estimulación cerebral profunda (DBS) se ha propuesto como una alternativa terapéutica para el manejo de la depresión resistente al tratamiento (DRT). Sin embargo, existen múltiples blancos para neuroestimulación y se desconoce el punto neuroanatómico óptimo en esta patología. Como parte del circuito de recompensa, el núcleo accumbens (NAc) ha sido estudiado en modelos de depresión y anhedonia. El objetivo de este artículo fue describir la experiencia clínica de la implantación de electrodos bilaterales de DBS en el NAc. REPORTE DE CASOS: Se describe la experiencia en cuatro mujeres entre los 17 a 41 años con DRT. Los casos presentaban antecedente de múltiples hospitalizaciones e intentos de suicidio serios, a pesar de haber sido tratadas previamente con terapia farmacológica, psicoterapia y TECAR (Terapia electroconvulsiva con anestesia y relajación). A los 6 meses del inicio del DBS, se observó una mejoría de los síntomas depresivos en la escala de Hamilton y un incremento en la escala de funcionalidad global. La anhedonia y la abulia persistieron luego de la cirugía, aunque con menor intensidad. CONCLUSIÓN: La DBS del NAc puede ser una estrategia efectiva en el tratamiento de pacientes con DRT, impactando en la funcionalidad y en la disminución del riesgo suicida.

INTRODUCTION: Deep brain stimulation (DBS) has been proposed as a therapeutic alternative for Treatment-resistant depression (TRD) patients. However, there are multiple targets for neurostimulation and the optimal neuroanatomical landmark for this pathology is unknown. Nucleus accumbens (NAc) is a crucial part of the reward circuit and has been studied extensively in models of depression and anhedonia. The objective of this study was to describe our clinical experience with DBS of the NAc patients with TRD. CASE SERIES: It described the experience in four females between 17 and 41 years of age. All cases presented with a history of multiple hospitalizations and serious suicide attempts, despite having been treated with optimal pharmacological regimes, psychotherapy and ECT (Electroconvulsive therapy). Six months after the initiation of DBS, an improvement in the Hamilton Depression Scale and in the Global Assessment of Functioning Scale was observed. Anhedonia and abulia persisted after the surgery, although less severe. CONCLUSION: DBS of NAc seems to offer favorable surgical outcomes in patients with TRD, impacting functionality and suicidal risk.

SHELL Part of Nucleus Accumbens and Its Laterality Has Important Role in Response to Chronic Stress in Female Rats

Abstract The nucleus accumbens shell (NAcSh) plays a role in appetitive and negative motivation with sex differences in responses. NAcSh and its laterality in metabolic and hormonal responses to chronic stress in female rats is evaluated via transient inactivation of this nucleus during stress induction. Animals in the stress groups received consecutive stress for four days and transient inactivation of NAcSh was performed by administrating lidocaine (0.2%) unilaterally or bilaterally in the nucleus for five minutes before electric foot shock induction. After stress termination, food and water intake, latency to eat, plasma glucose, corticosterone, estradiol and progesterone were measured in all groups. Results showed that stress increased food intake and blood glucose level, but there were no change in the latency to eat and the amount of water intake. The right side, the left side, and both sides of NAcSh may be dominant in latency to eat, food intake, and both water intake and plasma glucose level, respectively. Although chronic stress included no changes for corticosterone and progesterone, it increased estradiol level in plasma. Also, bilateral and right sides of NAcSh may have modulatory effects on stress in corticosterone and progesterone, respectively, without affecting estradiol. It can be concluded that the NAc shell plays a pivotal role in metabolic and hormonal responses to chronic stress in a laterality manner in female rats.

Ezrin-radixin-moesin proteins are regulated by Akt-GSK3β signaling in the rat nucleus accumbens core

The ezrin-radixin-moesin (ERM) proteins are a family of membrane-associated proteins known to play roles in cell-shape determination as well as in signaling pathways. We have previously shown that amphetamine decreases phosphorylation levels of these proteins in the nucleus accumbens (NAcc), an important neuronal substrate mediating rewarding effects of drugs of abuse. In the present study, we further examined what molecular pathways may be involved in this process. By direct microinjection of LY294002, a PI3 kinase inhibitor, or of S9 peptide, a proposed GSK3β activator, into the NAcc core, we found that phosphorylation levels of ERM as well as of GSK3β in this site are simultaneously decreased. These results indicate that ERM proteins are under the regulation of Akt-GSK3β signaling pathway in the NAcc core. The present findings have a significant implication to a novel signal pathway possibly leading to structural plasticity in relation with drug addiction.

Neural pathway between the nucleus accumbens and the rostral ventrolateral medulla in a rat model of anorexia nervosa / 南方医科大学学报

OBJECTIVE@#To investigate the potential neural pathway connecting the nucleus accumbens (NAc) and the rostral ventrolateral medulla (RVLM), and whether the pathway participates in the regulation of cardiovascular function in a model rat of anorexia nervosa (AN).@*METHODS@#Rat models of AN were established by allowing voluntary activity in a running wheel with restricted feeding, with the rats having free access to normal chow without exercise as the control group. FluoroGold (FG) retrograde tracing method and multi-channel simultaneous recording technique were used to explore the possible pathway between the NAc and the RVLM.@*RESULTS@#The rats in AN group exhibited significantly reduced systolic blood pressure (SBP), mean arterial pressure (MAP) and heart rate (HR) with significantly increased discharge frequency of RVLM neurons in comparison with the control rats. After the injection of FG into the RVLM, retrograde labeled neurons were observed in the NAc of the rats in both the normal control and AN groups. In both groups, SBP and HR were significantly decreased in response to 400 μA electrical stimulation of the NAc accompanied by an obvious increase in the discharge frequency of the RVLM neurons; the diastolic blood pressure (DBP) and MAP were significantly lower in AN model rats than in the normal rats in response to the stimulation.@*CONCLUSIONS@#We successfully established a rat model of AN via hyperactivity and restricted feeding and confirm the presence of a neural pathway connecting the NAc and the RVLM. This pathway might participate in the regulation of cardiovascular function in AN model rats.

Early-life stress alters sleep structure and the excitatory-inhibitory balance in the nucleus accumbens in aged mice / 中华医学杂志(英文版)

Background@#Exposure to adverse experiences in early life may profoundly reshape the neurodevelopmental trajectories of the brain and lead to long-lasting behavioral and neural alterations. One deleterious effect of early-life stress that manifests in later life is sleep disturbance, but this has not been examined in aged mice and the underlying neural mechanisms remain unknown. Considering the important role of the nucleus accumbens (NAc) in the sleep-wake regulation, this study aimed to assess the effects of early-life stress on the sleep behaviors in aged mice and the potential involvement of the NAc in stress-induced sleep abnormalities.@*Methods@#Twenty aged male C57BL/6 mice (>16 months, n = 10 per group) were used in this study. During post-natal days 2 to 9, dams were provided with either sufficient (control) or a limited nesting and bedding materials (stressed). When the mice were 16 to 17 months old, their sleep-wake behaviors were recorded over 24 h using electroencephalogram and electromyelogram. The amount of each sleep-wake stage, mean duration, and stage transition was analyzed. Then, five animals were randomly chosen from each group and were used to measure the expression levels of vesicular glutamate transporter-1 (VGluT1) and vesicular transporters of γ-aminobutyric acid (VGAT) in the NAc using immunohistochemistry. Group comparisons were carried out using Student t test or analysis of variances when appropriate.@*Results@#Compared with the control mice, the early-life stressed aged mice spent less time awake over 24 h (697.97 ± 77.47 min vs. 631.33 ± 34.73 min, t17 = 2.376, P = 0.030), accordingly, non-rapid eye movement sleep time was increased (667.37 ± 62.07 min vs. 723.54 ± 39.21 min, t17 = 2.326, P = 0.033) and mean duration of rapid eye movement sleep was prolonged (73.00 ± 8.98 min vs. 89.39 ± 12.69 min, t17 = 3.277, P = 0.004). Meanwhile, we observed decreased VGluT1/VGAT ratios in the NAc in the stressed group (F(1, 16) = 81.04, P < 0.001).@*Conclusion@#Early adverse experiences disrupt sleep behaviors in aged mice, which might be associated with the excitatory-inhibitory imbalance in the NAc.

Effects of γ-aminobutyric acid on feeding changes in rats and its potential mechanism / 中华行为医学与脑科学杂志

Objective@#To investigate whether γ-aminobutyric acid (GABA) receptor signaling pathway is involved in the regulation of thalamic undefined (ZI)-nucleus accumbens (NAc) neural pathways on gastric distraction (GD)-sensitive neuronal firing activity and the impact on food intake, the number of times and the frequency in rats.@*Methods@#Six rats were randomly selected and the neural pathway between ZI and NAc in rat thalamus was observed by fluorescent gold (FG) retrograde tracing method.Eighty-two rats were randomly selected, and the gastric balloon was placed in gastric cavity, the microelectrode was placed in the NAc, and the stimulating electrode was placed in the ZI. The single-cell discharge recording method was used to observe the effect of electrical stimulation ZI on the excitability of GD-sensitive neurons in rat NAc.Eighteen rats were randomly selected and were divided into three groups according to the random number table. They were NS group, GABA group, GABA + GABA receptor antagonist bicuculline (BIC) group with 6 in each group, and the rat NAc was used to embed the cannula. The method of GABA and BIC was injected to observe the changes of cumulative food intake in rats for 4 h. Eighteen rats were randomly selected and randomly divided into three groups: sham stimulation (SS) group, 50 μA electrical stimulation group, 50 μA electrical stimulation + BIC group with 6 in each group. The 4 h cumulative food intake of rats was observed by electro-stimulation of rat ZI and rat NAc injection of BIC.@*Results@#Fluorescent gold retrograde tracking combined with fluorescent immunohistochemical staining showed that there were visible GABA and fluorescent gold double labeled neurons in ZI. Electrical stimulation of ZI, the frequency of GABA-sensitive GD neurons in rat NAc increased significantly (GD-E increase: (78.8±8.4)%, GD-I increase: (89.3±9.2)%, P<0.01), but the inhibitory effect was antagonized by BIC (GD-E increase: (113.8±13.6)%, GD-I increase: (121.8±14.2)%, P<0.01). Microinjection of GABA in rat NAc significantly increased the cumulative food intake for 4 h ((155.72±18.84) kcal, t=3.41, P<0.05), which was antagonized by partial BIC (123.43±15.11) kcal, t=3.28, P<0.05). Electrical stimulation of ZI significantly increased the food intake in rats ((39.07±11.27) kcal, t=2.96, P<0.05), and this effect can be partially antagonized by BIC ((34.17±10.85)kcal, t=2.33, P<0.05).@*Conclusion@#The ZI-NAc neural pathway regulates the discharge activity of rat gastric distension (GD)-sensitive neurons and the feeding status of rats, and the GABA receptor signaling pathway may be involved in mediating the process.

Effects of γ-aminobutyric acid on feeding changes in rats and its potential mechanism / 中华行为医学与脑科学杂志

Objective To investigate whether γ-aminobutyric acid (GABA) receptor signaling pathway is involved in the regulation of thalamic undefined (ZI)-nucleus accumbens (NAc) neural pathways on gastric distraction (GD)-sensitive neuronal firing activity and the impact on food intake,the number of times and the frequency in rats.Methods Six rats were randomly selected and the neural pathway between Zl and NAc in rat thalamus was observed by fluorescent gold (FG) retrograde tracing method.Eighty-two rats were randomly selected,and the gastric balloon was placed in gastric cavity,the microelectrode was placed in the NAc,and the stimulating electrode was placed in the ZI.The single-cell discharge recording method was used to observe the effect of electrical stimulation ZI on the excitability of GD-sensitive neurons in rat NAc.Eighteen rats were randomly selected and were divided into three groups according to the random number table.They were NS group,GABA group,GABA + GABA receptor antagonist bicuculline (BIC) group with 6 in each group,and the rat NAc was used to embed the cannula.The method of GABA and BIC was injected to observe the changes of cumulative food intake in rats for 4 h.Eighteen rats were randomly selected and randomly divided into three groups:sham stimulation (SS) group,50 μA electrical stimulation group,50 μA electrical stimulation + BIC group with 6 in each group.The 4 h cumulative food intake of rats was observed by electro-stimulation of rat ZI and rat NAc injection of BIC.Results Fluorescent gold retrograde tracking combined with fluorescent immunohistochemical staining showed that there were visible GABA and fluorescent gold double labeled neurons in ZI.Electrical stimulation of ZI,the frequency of GABA-sensitive GD neurons in rat NAc increased significantly (GD-E increase:(78.8±8.4) ％,GD-I increase:(89.3±9.2) ％,P＜0.01),but the inhibitory effect was antagonized by BIC (GD-E increase:(113.8 ± 13.6)％,GD-I increase:(121.8± 14.2)％,P＜0.01).Microinjection of GABA in rat NAc significantly increased the cumulative food intake for 4 h ((155.72± 18.84) kcal,t=3.41,P＜0.05),which was antagonized by partial BIC (123.43± 15.11) kcal,t =3.28,P＜ 0.05).Electrical stimulation of ZI significantly increased the food intake in rats ((39.07± 11.27) kcal,t =2.96,P＜0.05),and this effect can be partially antagonized by BIC ((34.17 ± 10.85) kcal,t =2.33,P＜ 0.05).Conclusion The ZI-NAc neural pathway regulates the discharge activity of rat gastric distension (GD)-sensitive neurons and the feeding status of rats,and the GABA receptor signaling pathway may be involved in mediating the process.