The contribution of basal ganglia outputs to consummatory behavior remains poorly understood. We recorded from the substantia nigra pars reticulata (SNR), the major basal ganglia output nucleus, ...during self-initiated drinking in mice. The firing rates of many lateral SNR neurons were time-locked to individual licks. These neurons send GABAergic projections to the deep layers of the orofacial region of the lateral tectum (superior colliculus, SC). Many tectal neurons were also time-locked to licking, but their activity was usually in antiphase with that of SNR neurons, suggesting inhibitory nigrotectal projections. We used optogenetics to selectively activate the GABAergic nigrotectal afferents in the deep layers of the SC. Photo-stimulation of the nigrotectal projections transiently inhibited the activity of the lick-related tectal neurons, disrupted their licking-related oscillatory pattern and suppressed self-initiated drinking. These results demonstrate that GABAergic nigrotectal projections have a crucial role in coordinating drinking behavior.
Although glucagon-like peptide 1 (GLP-1) is known to regulate feeding, the central mechanisms contributing to this function remain enigmatic. Here, we aim to test the role of neurons expressing GLP-1 ...receptors (GLP-1R) in the dorsolateral septum (dLS; dLSGLP−1R) that project to the lateral hypothalamic area (LHA) on food intake and determine the relationship with feeding regulation.
Using chemogenetic manipulations, we assessed how activation or inhibition of dLSGLP−1R neurons affected food intake in Glp1r-ires-Cre mice. Then, we used channelrhodopsin-assisted circuit mapping, chemogenetics, and electrophysiological recordings to identify and assess the role of the pathway from dLSGLP−1R →LHA projections in regulating food intake.
Chemogenetic inhibition of dLSGLP−1R neurons increases food intake. LHA is a major downstream target of dLSGLP−1R neurons. The dLSGLP−1R→LHA projections are GABAergic, and chemogenetic inhibition of this pathway also promotes food intake. While chemogenetic activation of dLSGLP−1R→LHA projections modestly decreases food intake, optogenetic stimulation of the dLSGLP−1R→LHA projection terminals in the LHA rapidly suppresses feeding behavior. Finally, we demonstrate that the GLP-1R agonist, Exendin 4 enhances dLSGLP−1R →LHA GABA release.
Together, these results demonstrate that dLS-GLP-1R neurons and the inhibitory pathway to LHA can regulate feeding behavior, which might serve as a potential therapeutic target for the treatment of eating disorders or obesity.
•Chemogenetic inhibition of dLSGLP−1R neurons boosts food intake in mice.•dLSGLP−1R neurons project to LHA and release GABA.•Optogenetic activation of dLSGLP−1R → LHA axonal terminals suppresses food intake.•GLP-1R agonism enhances dLSGLP−1R → LHA GABA release via a presynaptic mechanism.
µ-Opioid peptide receptor (MOPR) stimulation alters respiration, analgesia and reward behaviour, and can induce substance abuse and overdose
. Despite its evident importance, the endogenous ...mechanisms for MOPR regulation of consummatory behaviour have remained unknown
. Here we report that endogenous MOPR regulation of reward consumption in mice acts through a specific dorsal raphe to nucleus accumbens projection. MOPR-mediated inhibition of raphe terminals is necessary and sufficient to determine consummatory response, while select enkephalin-containing nucleus accumbens ensembles are engaged prior to reward consumption, suggesting that local enkephalin release is the source of the endogenous MOPR ligand. Selective modulation of nucleus accumbens enkephalin neurons and CRISPR-Cas9-mediated disruption of enkephalin substantiate this finding. These results isolate a fundamental endogenous opioid circuit for state-dependent consumptive behaviour and suggest alternative mechanisms for opiate modulation of reward.
Unilateral dopamine (DA) depletion produces ipsiversive turning behaviour, and the injection of DA receptor agonists can produce contraversive turning, but the underlying mechanisms remain unclear. ...We conducted in vivo recording and pharmacological and optogenetic manipulations to study the role of DA and striatal output in turning behaviour. We used a video‐based tracking programme while recording single unit activity in both putative medium spiny projection neurons (MSNs) and fast‐spiking interneurons (FSIs) in the dorsal striatum bilaterally. Our results suggest that unilateral DA depletion reduced striatal output from the depleted side, resulting in asymmetric striatal output. Depletion systematically altered activity in both MSNs and FSIs, especially in neurons that increased firing during turning movements. Like D1 agonist SKF 38393, optogenetic stimulation in the depleted striatum increased striatal output and reversed biassed turning. These results suggest that relative striatal outputs from the two cerebral hemispheres determine the direction of turning: Mice turn away from the side of higher striatal output and towards the side of the lower striatal output.
Unilateral dopamine depletion produces abnormal turning behaviour, but the underlying mechanisms remain controversial. We recorded single unit activity in the dorsal striatum bilaterally during pharmacological and optogenetic manipulations, while characterizing detailed parameters of turning behaviour. Our results further highlight the role of dopamine in movement initiation and suggest that the relative striatal outputs from the two cerebral hemispheres determine turning direction.
The timing of actions is critical for adaptive behavior. In this study we measured neural activity in the substantia nigra as mice learned to change their action duration to earn food rewards. We ...observed dramatic changes in single unit activity during learning: both dopaminergic and GABAergic neurons changed their activity in relation to behavior to reflect the learned instrumental contingency and the action duration. We found the emergence of "action-on" neurons that increased firing for the duration of the lever press and mirror-image "action-off" neurons that paused at the same time. This pattern is especially common among GABAergic neurons. The activity of many neurons also reflected confidence about the just completed action and the prospect of reward. Being correlated with the relative duration of the completed action, their activity could predict the likelihood of reward collection. Compared with the GABAergic neurons, the activity of dopaminergic neurons was more commonly modulated by the discriminative stimulus signaling the start of each trial, suggesting that their phasic activity reflected sensory salience rather than any reward prediction error found in previous work. In short, these results suggest that (1) nigral activity is highly plastic and modified by the learning of the instrumental contingency; (2) GABAergic output from the substantia nigra can simultaneously inhibit and disinhibit downstream structures, while the dopaminergic output also provide bidirectional modulation of the corticostriatal circuits; (3) dopaminergic and GABAergic neurons show similar task-related activity, although DA neurons are more responsive to the trial start signal.
Disorders implicating the basal ganglia are often characterized by postural deficits, but little is known about the role of the basal ganglia in posture control. Using wireless multi‐electrode ...recording, we measured single unit activity from GABAergic and dopaminergic neurons in the substantia nigra as unrestrained mice stood on an elevated platform while introducing continuous postural disturbances in the roll plane. We found two major types of neurons – those activated by tilt to the left side of the body and suppressed by tilt to the right side, and others activated by tilt to the right side and suppressed by tilt to the left side. Contrary to the prevailing view that the basal ganglia output from the substantia nigra pars reticulata either inhibits or disinhibits downstream structures in an all or none fashion, we showed that it continuously sends anti‐phase signals to their downstream targets. We also demonstrated for the first time that nigrostriatal dopaminergic transmission is modulated by postural disturbances.
Using wireless multi‐electrode recording, we measured single unit activity from GABAergic and dopaminergic neurons in the substantia nigra as unrestrained mice stood on an elevated platform while introducing continuous postural disturbances in the roll plane. We found two major types of neurons: those activated by tilt to the left side of the body and suppressed by tilt to the right side, and others activated by tilt to the right side and suppressed by tilt to the left side.
Maternal overnutrition is associated with adverse outcomes in offspring, including increased risk for obesity and diabetes. Here, we aim to test the effects of maternal obesity on lateral ...hypothalamic feeding circuit function and determine the relationship with body weight regulation.
Using a mouse model of maternal obesity, we assessed how perinatal overnutrition affected food intake and body weight regulation in adult offspring. We then used channelrhodopsin-assisted circuit mapping and electrophysiological recordings to assess the synaptic connectivity within an extended amygdala-lateral hypothalamic pathway.
We show that maternal overnutrition during gestation and throughout lactation produces offspring that are heavier than controls prior to weaning. When weaned onto chow, the body weights of over-nourished offspring normalize to control levels. However, when presented with highly palatable food as adults, both male and female maternally over-nourished offspring are highly susceptible to diet-induced obesity. This is associated with altered synaptic strength in an extended amygdala-lateral hypothalamic pathway, which is predicted by developmental growth rate. Additionally, lateral hypothalamic neurons receiving synaptic input from the bed nucleus of the stria terminalis have enhanced excitatory input following maternal overnutrition which is predicted by early life growth rate.
Together, these results demonstrate one way in which maternal obesity rewires hypothalamic feeding circuits to predispose offspring to metabolic dysfunction.
•Maternal overnutrition yields hyperphagic and obesity-prone offspring.•Maternal overnutrition increases excitatory input in the BNST→LHA pathway•Early life growth rate predicts synaptic strength in the BNST→LHA pathway
MicroRNAs and siRNAs interact with target sequences in mRNAs, inducing cleavage- and non-cleavage-based gene repression through the RNA-induced silencing complex (RISC) that consists of one of four ...mammalian Argonaute proteins, Ago1-Ago4. The process of how Dicer substrate small hairpin RNAs (shRNAs) are loaded into different mammalian Agos in vivo is not well established. Here we report that shRNAs are loaded into mammalian Agos in two stepwise processes, physical association and activation, with the latter being the rate-limiting step with noncleaving RISC. We establish that, although RNA duplexes processed from shRNAs bind to Agos in cells with similar affinity, the degree by which the complexes are activated (coupled with the removal of the passenger strand) correlates with the thermodynamic instability of RNA duplexes being loaded rather than the structure of the RNA, as was previously demonstrated in DROSOPHILA: Interestingly, Ago loading of siRNAs is less sensitive to thermostability than that of their shRNA equivalents. These results may have important implications for the future design of RNAi-based therapeutics.
Contextual drug-associated memories precipitate craving and relapse in cocaine users. Such associative memories can be weakened through interference with memory reconsolidation, a process by which ...memories are maintained following memory retrieval-induced destabilization. We hypothesized that cocaine-memory reconsolidation requires cannabinoid type 1 receptor (CB1R) signaling based on the fundamental role of the endocannabinoid system in synaptic plasticity and emotional memory processing. Using an instrumental model of cocaine relapse, we evaluated whether systemic CB1R antagonism (AM251; 3 mg/kg, i.p.) during memory reconsolidation altered (1) subsequent drug context-induced cocaine-seeking behavior as well as (2) cellular adaptations and (3) excitatory synaptic physiology in the basolateral amygdala (BLA) in male Sprague Dawley rats. Systemic CB1R antagonism, during, but not after, cocaine-memory reconsolidation reduced drug context-induced cocaine-seeking behavior 3 d, but not three weeks, later. CB1R antagonism also inhibited memory retrieval-associated increases in BLA zinc finger 268 (zif268) and activity regulated cytoskeletal-associated protein (Arc) immediate-early gene (IEG) expression and changes in BLA AMPA receptor (AMPAR) and NMDA receptor (NMDAR) subunit phosphorylation that likely contribute to increased receptor membrane trafficking and synaptic plasticity during memory reconsolidation. Furthermore, CB1R antagonism increased memory reconsolidation-associated spontaneous EPSC (sEPSC) frequency in BLA principal neurons during memory reconsolidation. Together, these findings suggest that CB1R signaling modulates cellular and synaptic mechanisms in the BLA that may facilitate cocaine-memory strength by enhancing reconsolidation or synaptic reentry reinforcement, or by inhibiting extinction-memory consolidation. These findings identify the CB1R as a potential therapeutic target for relapse prevention.
Drug relapse can be triggered by the retrieval of context-drug memories on re-exposure to a drug-associated environment. Context-drug associative memories become destabilized on retrieval and must be reconsolidated into long-term memory stores to persist. Hence, targeted interference with memory reconsolidation can weaken maladaptive context-drug memories and reduce the propensity for drug relapse. Our findings indicate that cannabinoid type 1 receptor (CB1R) signaling is critical for context-cocaine memory reconsolidation and subsequent drug context-induced reinstatement of cocaine-seeking behavior. Furthermore, cocaine-memory reconsolidation is associated with CB1R-dependent immediate-early gene (IEG) expression and changes in excitatory synaptic proteins and physiology in the basolateral amygdala (BLA). Together, our findings provide initial support for CB1R as a potential therapeutic target for relapse prevention.
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