Science advances
2021 Nov 19
Meinhardt, MW;Pfarr, S;Fouquet, G;Rohleder, C;Meinhardt, ML;Barroso-Flores, J;Hoffmann, R;Jeanblanc, J;Paul, E;Wagner, K;Hansson, AC;Köhr, G;Meier, N;von Bohlen Und Halbach, O;Bell, RL;Endepols, H;Neumaier, B;Schönig, K;Bartsch, D;Naassila, M;Spanagel, R;Sommer, WH;
PMID: 34788104 | DOI: 10.1126/sciadv.abh2399
[Figure: see text].
J Neuroendocrinol. 2018 Oct 26:e12653.
2018 Oct 26
Stubbs FE, Conway-Campbell BL, Lightman SL.
PMID: 30362285 | DOI: 10.1111/jne.12653
Since the 1950's (1) the systems level interactions between the hypothalamus, pituitary and end organs such as the adrenal, thyroid and gonads have been well known, however it is only over the last three decades that advances in molecular biology and information technology have provided a tremendous expansion of knowledge at the molecular level.
Cell reports
2023 Apr 20
Chao, YS;Parrilla-Carrero, J;Eid, M;Culver, OP;Jackson, TB;Lipat, R;Taniguchi, M;Jhou, TC;
PMID: 37083325 | DOI: 10.1016/j.celrep.2023.112404
Cocaine blocks dopamine reuptake, thereby producing rewarding effects that are widely studied. However, cocaine also blocks serotonin uptake, which we show drives, in rats, individually variable aversive effects thatdepend on serotonin 2C receptors (5-HT2CRs) in the rostromedial tegmental nucleus (RMTg), a major GABAergic afferent to midbrain dopamine neurons. 5-HT2CRs produce depolarizing effects in RMTg neuronsthat are particularly strong in some rats, leading to aversive effects that reduce acquisition of and relapse to cocaine seeking. In contrast, 5-HT2CR signaling is largely lost after cocaine exposure in other rats, leading to reduced aversive effects and increased cocaine seeking. These results suggest a serotonergic biological marker of cocaine-seeking vulnerability that can be targeted to modulate drug seeking.
STAR protocols
2022 Mar 18
Althammer, F;Krause, EG;de Kloet, AD;Smith, J;Grinevich, V;Charlet, A;Stern, JE;
PMID: 35199030 | DOI: 10.1016/j.xpro.2022.101160
Here, we present a step-by-step protocol for three-dimensional reconstruction of astrocyte morphology, applied to the central amygdala oxytocin receptor-expressing astrocytes. This includes RNAse-free perfusion, combination of RNAscope and immunohistochemistry, and confocal imaging. This protocol provides detailed information about tissue handling and a comprehensive description of the RNAScope technique to label rat and mouse oxytocin receptor mRNA. We also describe three-dimensional reconstruction that allows the assessment of more than 70 different cellular parameters, powerful for studying astrocyte morphology and astrocyte-astrocyte interactions. For complete details on the use and execution of this protocol, please refer to Wahis etal. (2021) and Althammer etal. (2020).
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
2021 Dec 18
You, ZB;Galaj, E;Alén, F;Wang, B;Bi, GH;Moore, AR;Buck, T;Crissman, M;Pari, S;Xi, ZX;Leggio, L;Wise, RA;Gardner, EL;
PMID: 34923576 | DOI: 10.1038/s41386-021-01249-2
Cocaine addiction is a significant medical and public concern. Despite decades of research effort, development of pharmacotherapy for cocaine use disorder remains largely unsuccessful. This may be partially due to insufficient understanding of the complex biological mechanisms involved in the pathophysiology of this disorder. In the present study, we show that: (1) elevation of ghrelin by cocaine plays a critical role in maintenance of cocaine self-administration and cocaine-seeking motivated by cocaine-conditioned stimuli; (2) acquisition of cocaine-taking behavior is associated with the acquisition of stimulatory effects of cocaine by cocaine-conditioned stimuli on ghrelin secretion, and with an upregulation of ghrelin receptor mRNA levels in the ventral tegmental area (VTA); (3) blockade of ghrelin signaling by pretreatment with JMV2959, a selective ghrelin receptor antagonist, dose-dependently inhibits reinstatement of cocaine-seeking triggered by either cocaine or yohimbine in behaviorally extinguished animals with a history of cocaine self-administration; (4) JMV2959 pretreatment also inhibits brain stimulation reward (BSR) and cocaine-potentiated BSR maintained by optogenetic stimulation of VTA dopamine neurons in DAT-Cre mice; (5) blockade of peripheral adrenergic β1 receptors by atenolol potently attenuates the elevation in circulating ghrelin induced by cocaineandinhibits cocaine self-administration and cocaine reinstatement triggered by cocaine. These findings demonstrate that the endogenous ghrelin system plays an important role in cocaine-related addictive behaviors and suggest that manipulating and targeting this system may be viable for mitigating cocaine use disorder.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
2023 May 23
Glover, EJ;Margaret Starr, E;Gascon, A;Clayton-Stiglbauer, K;Amegashie, CL;Selchick, AH;Vaughan, DT;Wayman, WN;Woodward, JJ;Judson Chandler, L;
PMID: 37221326 | DOI: 10.1038/s41386-023-01612-5
The rostromedial tegmental nucleus (RMTg) encodes negative reward prediction error (RPE) and plays an important role in guiding behavioral responding to aversive stimuli. Previous research has focused on regulation of RMTg activity by the lateral habenula despite studies revealing RMTg afferents from other regions including the frontal cortex. The current study provides a detailed anatomical and functional analysis of cortical input to the RMTg of male rats. Retrograde tracing uncovered dense cortical input to the RMTg spanning the medial prefrontal cortex, the orbitofrontal cortex and anterior insular cortex. Afferents were most dense in the dorsomedial subregion of the PFC (dmPFC), an area that is also implicated in both RPE signaling and aversive responding. RMTg-projecting dmPFC neurons originate in layer V, are glutamatergic, and collateralize to select brain regions. In-situ mRNA hybridization revealed that neurons in this circuit are predominantly D1 receptor-expressing with a high degree of D2 receptor colocalization. Consistent with cFos induction in this neural circuit during exposure to foot shock and shock-predictive cues, optogenetic stimulation of dmPFC terminals in the RMTg drove avoidance. Lastly, acute slice electrophysiology and morphological studies revealed that exposure to repeated foot shock resulted in significant physiological and structural changes consistent with a loss of top-down modulation of RMTg-mediated signaling. Altogether, these data reveal the presence of a prominent cortico-subcortical projection involved in adaptive behavioral responding to aversive stimuli such as foot shock and provide a foundation for future work aimed at exploring alterations in circuit function in diseases characterized by deficits in cognitive control over reward and aversion.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
2023 Feb 04
Domi, E;Xu, L;Toivainen, S;Wiskerke, J;Coppola, A;Holm, L;Augier, E;Petrella, M;Heilig, M;
PMID: 36739350 | DOI: 10.1038/s41386-023-01543-1
Alcohol use despite negative consequences is a core phenomenon of alcohol addiction. We recently used alcohol self-administration that is resistant to footshock punishment as a model of this behavior, and found that activity of PKCδ + GABAergic neurons in the central amygdala (CeA) is a determinant of individual susceptibility for punishment resistance. In the present study, we examined whether activation of GABAB receptors in CeA can attenuate the activity of PKCδ + neurons in this region, and whether this will result in suppression of punishment- resistant alcohol self-administration in the minority of rats that show this behavior. Systemic administration of the clinically approved GABAB agonist baclofen (1 and 3 mg/kg) dose- dependently reduced punishment-resistant alcohol self-administration. Bilateral microinjections of baclofen into CeA (64 ng in 0.3 µl/side) reduced the activity of PKCδ + neurons, as measured by Fos expression. This manipulation also selectively suppressed punished alcohol self-administration in punishment-resistant rats. Expression analysis indicated that virtually all CeA PKCδ + neurons express the GABAB receptor. Using in vitro electrophysiology, we found that baclofen induced hyperpolarization of CeA neurons, reducing their firing rate in response to depolarizing current injections. Together, our findings provide a potential mechanism that contributes to the clinical efficacy of baclofen in alcohol addiction. Therapeutic use of baclofen itself is limited by problems of tolerance and need for dose escalation. Our findings support a mechanistic rationale for developing novel, improved alcohol addiction medications that target GABAB receptors, and that lack these limitations, such as e.g., GABAB positive allosteric modulators (PAM:s).
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
2023 Jan 12
Velazquez-Sanchez, C;Muresan, L;Marti-Prats, L;Belin, D;
PMID: 36635597 | DOI: 10.1038/s41386-022-01522-y
Some compulsive disorders have been considered to stem from the loss of control over coping strategies, such as displacement. However, the cellular mechanisms involved in the acquisition of coping behaviours and their subsequent compulsive manifestation in vulnerable individuals have not been elucidated. Considering the role of the locus coeruleus (LC) noradrenaline-dependent system in stress and related excessive behaviours, we hypothesised that neuroplastic changes in the LC may be associated with the acquisition of an adjunctive polydipsic water drinking, a prototypical displacement behaviour, and the ensuing development of compulsion in vulnerable individuals. Thus, male Sprague Dawley rats were characterised for their tendency, or not, to develop compulsive polydipsic drinking in a schedule-induced polydipsia (SIP) procedure before their fresh brains were harvested. A new quantification tool for RNAscope assays revealed that the development of compulsive adjunctive behaviour was associated with a low mRNA copy number of the plasticity marker Arc in the LC which appeared to be driven by specific adaptations in an ensemble of tyrosine hydroxylase (TH)+, zif268- neurons. This ensemble was specifically engaged by the expression of compulsive adjunctive behaviour, not by stress, because its functional recruitment was not observed in individuals that no longer had access to the water bottle before sacrifice, while it consistently correlated with the levels of polydipsic water drinking only when it had become compulsive. Together these findings suggest that downregulation of Arc mRNA levels in a population of a TH+/zif268- LC neurons represents a signature of the tendency to develop compulsive coping behaviours.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
2022 Sep 08
McNulty, CJ;Fallon, IP;Amat, J;Sanchez, RJ;Leslie, NR;Root, DH;Maier, SF;Baratta, MV;
PMID: 36076018 | DOI: 10.1038/s41386-022-01443-w
Stress-linked disorders are more prevalent in women than in men and differ in their clinical presentation. Thus, investigating sex differences in factors that promote susceptibility or resilience to stress outcomes, and the circuit elements that mediate their effects, is important. In male rats, instrumental control over stressors engages a corticostriatal system involving the prelimbic cortex (PL) and dorsomedial striatum (DMS) that prevent many of the sequelae of stress exposure. Interestingly, control does not buffer against stress outcomes in females, and here, we provide evidence that the instrumental controlling response in females is supported instead by the dorsolateral striatum (DLS). Additionally, we used in vivo microdialysis, fluorescent in situ hybridization, and receptor subtype pharmacology to examine the contribution of prefrontal dopamine (DA) to the differential impact of behavioral control. Although both sexes preferentially expressed D1 receptor mRNA in PL GABAergic neurons, there were robust sex differences in the dynamic properties of prefrontal DA during controllable stress. Behavioral control potently attenuated stress-induced DA efflux in males, but not females, who showed a sustained DA increase throughout the entire stress session. Importantly, PL D1 receptor blockade (SCH 23390) shifted the proportion of striatal activity from the DLS to the DMS in females and produced the protective effects of behavioral control. These findings suggest a sex-selective mechanism in which elevated DA in the PL biases instrumental responding towards prefrontal-independent striatal circuitry, thereby eliminating the protective impact of coping with stress.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
2022 Feb 26
Rieger, NS;Varela, JA;Ng, AJ;Granata, L;Djerdjaj, A;Brenhouse, HC;Christianson, JP;
PMID: 35220413 | DOI: 10.1038/s41386-022-01292-7
Impairments in identifying and responding to the emotions of others manifest in a variety of psychopathologies. Therefore, elaborating the neurobiological mechanisms that underpin social responses to social emotions, or social affective behavior, is a translationally important goal. The insular cortex is consistently implicated in stress-related social and anxiety disorders, which are associated with diminished ability to make and use inferences about the emotions of others to guide behavior. We investigated how corticotropin-releasing factor (CRF), a neuromodulator evoked upon exposure to stressed conspecifics, influenced the insula. We hypothesized that social affective behavior requires CRF signaling in the insular cortex in order to detect stress in social interactions. In acute slices from male and female rats, CRF depolarized insular pyramidal neurons. In males, but not females, CRF suppressed presynaptic GABAergic inhibition leading to greater excitatory synaptic efficacy in a CRF receptor 1 (CRF1)- and cannabinoid receptor 1 (CB1)-dependent fashion. In males only, insular CRF increased social investigation, and CRF1 and CB1 antagonists interfered with social interactions with stressed conspecifics. To investigate the molecular and cellular basis for the effect of CRF we examined insular CRF1 and CB1 mRNAs and found greater total insula CRF1 mRNA in females but greater CRF1 and CB1 mRNA colocalization in male insular cortex glutamatergic neurons that suggest complex, sex-specific organization of CRF and endocannabinoid systems. Together these results reveal a new mechanism by which stress and affect contribute to social affective behavior.
