Dreadd*

Subjects are often willing to pay a cost for information. In a procedure that promotes paradoxical choices, animals choose between a richer option followed by a cue that is rewarded 50% of the time (No Info) vs. a leaner option followed by one of two cues that signal certain outcomes: one always rewarded (100%) and the other never rewarded, 0% (Info). Since decisions involve comparing the subjective value of options after integrating all their features, preference for information may rely on cortico-amygdalar circuitry...

The hippocampus is crucial for acquiring and retrieving episodic and contextual memories. In previous studies, the inactivation of dentate gyrus (DG) neurons by chemogenetic- and optogenetic-mediated hyperpolarization led to opposing conclusions about DG's role in memory retrieval. One study used Designer Receptors Exclusively Activated by Designer Drugs (DREADD)-mediated clozapine N-oxide (CNO)-induced hyperpolarization and reported that the previously formed memory was erased, thus concluding that denate gyrus is needed for memory maintenance...

BACKGROUND: Dynamic changes in neuronal activity and in noradrenergic locus coeruleus (LC) projections have been proposed during the transition from acute to chronic pain. Thus, we explored the cellular cFos activity of the LC and its projections, in conjunction with spontaneous pain-like behavior in neuropathic rats. METHODS: Tyrosine hydroxylase:Cre and wild-type Long-Evans rats, males and females, were subjected to chronic constriction injury (CCI) for 2 (short-term, CCI-ST) or 30 days (long-term, CCI-LT), evaluating cFos and Fluoro-Gold expression in the LC, and its projections to the spinal cord (SC) and rostral anterior cingulate cortex (rACC)...

Traumatic Brain Injury (TBI) patients frequently experience chronic pain that can enhance their suffering and significantly impair rehabilitative efforts. Clinical studies suggest that damage to the periaqueductal grey matter (PAG) following TBI, a principal center involved in endogenous pain control, may underlie the development of chronic pain. We hypothesized that TBI would diminish the usual pain control functions of the PAG, but that directly stimulating this center using a chemogenetic approach would restore descending pain modulation...

Neurodegenerative diseases are progressive disorders characterized by synaptic loss and neuronal death. Optogenetics combines optical and genetic methods to control the activity of specific cell types. The efficacy of this approach in neurodegenerative diseases has been investigated in many reviews, however, none of them tackled it systematically. Our study aimed to review systematically the findings of optogenetics and its potential applications in animal models of chronic neurodegenerative diseases and compare it with deep brain stimulation and designer receptors exclusively activated by designer drugs techniques...

GABAergic interneuron deficits have been implicated in the epileptogenesis of multiple neurological diseases. While epileptic seizures are a key clinical hallmark of CLN2 disease, a childhood-onset neurodegenerative lysosomal storage disorder caused by a deficiency of tripeptidyl peptidase 1 (TPP1), the etiology of these seizures remains elusive. Given that Cln2 R207X/R207X mice display fatal spontaneous seizures and an early loss of several cortical interneuron populations, we hypothesized that those two events might be causally related...

Interneuron loss is a prominent feature of temporal lobe epilepsy in both animals and humans and is hypothesized to be critical for epileptogenesis. As loss occurs concurrently with numerous other potentially pro-epileptogenic changes, however, the impact of interneuron loss in isolation remains unclear. For the present study, we developed an intersectional genetic approach to induce bilateral diphtheria toxin-mediated deletion of Vgat-expressing interneurons from dorsal and ventral hippocampus. In a separate group of mice, the same population was targeted for transient neuronal silencing with DREADDs...

The hippocampus has a central role in regulating contextual processes in memory. We have shown that pharmacological inactivation of ventral hippocampus (VH) attenuates the context-dependence of signaled active avoidance (SAA) in rats. Here, we explore whether the VH mediates intertrial responses (ITRs), which are putative unreinforced avoidance responses that occur between trials. First, we examined whether VH inactivation would affect ITRs. Male rats underwent SAA training and subsequently received intra-VH infusions of saline or muscimol before retrieval tests in the training context...

UNLABELLED: Blunted sensitivity to ethanol's aversive effects can increase motivation to consume ethanol; yet, the neurobiological circuits responsible for encoding these aversive properties are not fully understood. Plasticity in cells projecting from the insular cortex (IC) to the basolateral amygdala (BLA) is critical for taste aversion learning and retrieval, suggesting this circuit's potential involvement in modulating the aversive properties of ethanol. Here, we tested the hypothesis that GABAergic activity onto IC-BLA projections would be facilitated following the retrieval of an ethanol-conditioned taste aversion (CTA)...

BACKGROUND: Binge drinking, characterized by heavy episodic alcohol consumption, poses significant health hazards and increases the likelihood of developing an alcohol use disorder (AUD). Given the growing prevalence of this behavior and its negative consequences, there is a need to explore novel therapeutic targets. Accumulating evidence suggests that cholinergic interneurons (CIN) within the shell region of the nucleus accumbens (NAcSh) play a critical role in reward and addiction. However, their specific involvement in binge alcohol administration remains unclear...

The specific roles that different types of neurons play in recovery from injury is poorly understood. Here, we show that increasing the excitability of ipsilaterally projecting, excitatory V2a neurons using designer receptors exclusively activated by designer drugs (DREADDs) restores rhythmic bursting activity to a previously paralyzed diaphragm within hours, days, or weeks following a C2 hemisection injury. Further, decreasing the excitability of V2a neurons impairs tonic diaphragm activity after injury as well as activation of inspiratory activity by chemosensory stimulation, but does not impact breathing at rest in healthy animals...

UNLABELLED: Mammalian parenting is an unusually demanding commitment. How did evolution co-opt the reward system to ensure parental care? Previous work has implicated the lateral habenula (LHb), an epithalamic nucleus, as a potential intersection of parenting behavior and reward. Here, we examine the role of the LHb in the maternal behavior of naturally parturient mouse dams. We show that kainic acid lesions of the LHb induced a severe maternal neglect phenotype in dams towards their biological pups...

Environmental stimuli elicit drug craving and relapse in cocaine users by triggering the retrieval of strong cocaine-related contextual memories. Retrieval can also destabilize drug memories, requiring reconsolidation, a protein synthesis-dependent storage process, to maintain memory strength. Corticotropin-releasing factor (CRF) signaling in the basolateral amygdala (BLA) is necessary for cocaine-memory reconsolidation. We have hypothesized that a critical source of CRF in the BLA is the dorsal raphe nucleus (DR) based on its neurochemistry, anatomical connectivity, and requisite involvement in cocaine-memory reconsolidation...

Microglia actively survey the brain and dynamically interact with neurons to maintain brain homeostasis. Microglial Gi-protein coupled receptors (Gi-GPCRs) play a critical role in microglia-neuron communications. However, the impact of temporally activating microglial Gi signaling on microglial dynamics and neuronal activity in the homeostatic brain remains largely unknown. In this study, we employed Gi-based Designer Receptors Exclusively Activated by Designer Drugs (Gi-DREADD) to selectively and temporally modulate microglial Gi signaling pathway...

Rationale: Noxious stimuli are often perceived as itchy in patients with chronic dermatitis (CD); however, itch and pain mechanisms of CD are not known. Methods: TRPV1 involvement in CD was analyzed using a SADBE induced CD-like mouse model, and several loss- and gain-of-function mouse models. Trigeminal TRPV1 channel and MrgprA3+ neuron functions were analyzed by calcium imaging and whole-cell patch-clamp recordings. Lesional CD-like skin from mice were analyzed by unbiased metabolomic analysis. 20-HETE availability in human and mouse skin were determined by LC/MS and ELISA...

Previous work has demonstrated the importance of the prelimbic cortex (PL) in contextual control of operant behavior. However, the associated neural circuitry responsible for providing contextual information to the PL is not well understood. In Pavlovian fear conditioning the ventral hippocampus (vH) and its projection to the PL have been shown to be important in supporting the effects of context on learning. The present experiments used chemogenetic inhibition of the direct vH-PL projection or the vH to determine involvement in expression of context-specific operant behavior...

Deficits in cost/benefit decision making is a critical risk factor for gambling disorder. Reward-paired cues may play an important role, as these stimuli can enhance risk preference in rats. Despite extensive research implicating the dorsal striatum in the compulsive aspects of addiction, the role of nigrostriatal dopaminergic activity in cue-induced risk preference remains unclear, particularly in females. Accordingly, we examined the effects of manipulating the dopaminergic nigrostriatal pathway on cue-induced risky choice in female rats...

Spinal cord injury (SCI) is a devastating injury that causes permanent neurological dysfunction. To develop a new treatment strategy for SCI, a clinical trial of transplantation of human-induced pluripotent stem cell-derived neural precursor cells (NPCs) in patients in the subacute phase of SCI was recently initiated. The formation of synaptic connections with host neural tissues is one of the therapeutic mechanisms of cell transplantation, and this beneficial efficacy has been directly demonstrated using a chemogenetic tool...

Hyperaldosteronism is often associated with inappropriate aldosterone production and aldosterone synthase (Cyp11b2) expression. Normally, Cyp11b2 expression is limited to the adrenal zona glomerulosa (ZG) and regulated by angiotensin II which signals through Gq protein-coupled receptors. As cells migrate inwards, they differentiate into 11β-hydroxylase-expressing zona fasciculata (ZF) cells lacking Cyp11b2. The mechanism causing ZG-specific aldosterone biosynthesis is still unclear. We investigated the effect of chronic Gq signaling using transgenic mice with a clozapine N-oxide (CNO)-activated human M3 muscarinic receptor (DREADD) coupled to Gq (hM3Dq) that was expressed throughout the adrenal cortex...

Cortical electroencephalograms (EEG) may help understanding of neuropsychiatric illness and new treatment mechanisms. The aperiodic component (1/ f ) of EEG power spectra is often treated as noise, but recent studies suggest that changes to the aperiodic exponent of power spectra may reflect changes in excitation/inhibition balance, a concept linked to antidepressant effects, epilepsy, autism, and other clinical conditions. One confound of previous studies is behavioral state, because factors associated with behavioral state other than excitation/inhibition ratio may alter EEG parameters...