Major depressive disorder (MDD) is a complex and heterogeneous mood disorder, making it difficult to develop a generalized, pharmacological therapy that is effective for all who suffer from MDD. ...Through the fortuitous discovery of N-methyl-D-aspartate receptor (NMDAR) antagonists as effective antidepressants, we have gained key insights into how antidepressant effects can be produced at the circuit and molecular levels. NMDAR antagonists act as rapid-acting antidepressants such that relief from depressive symptoms occurs within hours of a single injection. The mode of action of NMDAR antagonists seemingly relies on their ability to activate protein-synthesis-dependent homeostatic mechanisms that restore top-down excitatory connections. Recent evidence suggests that NMDAR antagonists relieve depressive symptoms by forming new synapses resulting in increased excitatory drive. This event requires the mammalian target of rapamycin complex 1 (mTORC1), a signaling pathway that regulates synaptic protein synthesis. Herein, we review critical studies that shed light on the action of NMDAR antagonists as rapid-acting antidepressants and how they engage a neuron's or neural network's homeostatic mechanisms to self-correct. Recent studies notably demonstrate that a shift in γ-amino-butyric acid receptor B (GABA
R) function, from inhibitory to excitatory, is required for mTORC1-dependent translation with NMDAR antagonists. Finally, we discuss how GABA
R activation of mTORC1 helps resolve key discrepancies between rapid-acting antidepressants and local homeostatic mechanisms.
Alcohol use disorder (AUD) and anxiety/stressor disorders frequently co‐occur and this dual diagnosis represents a major health and economic problem worldwide. The basolateral amygdala (BLA) is a key ...brain region that is known to contribute to the aetiology of both disorders. Although many studies have implicated BLA hyperexcitability in the pathogenesis of AUD and comorbid conditions, relatively little is known about the specific efferent projections from this brain region that contribute to these disorders. Recent optogenetic studies have shown that the BLA sends a strong monosynaptic excitatory projection to the ventral hippocampus (vHC) and that this circuit modulates anxiety‐ and fear‐related behaviours. However, it is not known if this pathway influences alcohol drinking‐related behaviours. Here, we employed a rodent operant self‐administration regimen that procedurally separates appetitive (e.g. seeking) and consummatory (e.g., drinking) behaviours, chemogenetics and brain region‐specific microinjections, to determine if BLA‐vHC circuitry influences alcohol and sucrose drinking‐related measures. We first confirmed prior optogenetic findings that silencing this circuit reduced anxiety‐like behaviours on the elevated plus maze. We then demonstrated that inhibiting the BLA‐vHC pathway significantly reduced appetitive drinking‐related behaviours for both alcohol and sucrose while having no effect on consummatory measures. Taken together, these findings provide the first indication that the BLA‐vHC circuit may regulate appetitive reward seeking directed at alcohol and natural rewards and add to a growing body of evidence suggesting that dysregulation of this pathway may contribute to the pathophysiology of AUD and anxiety/stressor‐related disorders.
BACKGROUND: Although directly observed therapy (DOT) is recommended worldwide for monitoring anti-tuberculosis treatment, transportation and personnel requirements limit its use.OBJECTIVE: To ...evaluate the feasibility and acceptability of 'video DOT' (VDOT), which allows patients
to record and transmit medication ingestion via videos watched remotely by health care providers to document adherence.METHODS: We conducted a single-arm trial among tuberculosis (TB) patients in San Diego, California, USA, (n = 43) and Tijuana, Mexico (n = 9) to represent
high- and low-resource settings. Pre-/post-treatment interviews assessed participant characteristics and experiences. Adherence was defined as the proportion of observed doses to expected doses.RESULTS: The mean age was 37 years (range 18-86), 50% were male, and 88% were non-Caucasian.
The mean duration of VDOT use was 5.5 months (range 1-11). Adherence was similar in San Diego (93%) and Tijuana (96%). Compared to time on in-person DOT, 92% preferred VDOT, 81% thought VDOT was more confidential, 89% never/rarely had problems recording videos, and 100% would recommend
VDOT to others. Seven (13%) participants were returned to in-person DOT and six (12%) additional participants had their phones lost, broken or stolen.CONCLUSIONS: VDOT was feasible and acceptable, with high adherence in both high- and low-resource settings. Efficacy and cost-effectiveness studies are needed.
The mammalian/mechanistic target of rapamycin complex 1 (mTORC1) serves as a regulator of mRNA translation. Recent studies suggest that mTORC1 may also serve as a local, voltage sensor in the ...postsynaptic region of neurons. Considering biochemical, bioinformatics and imaging data, we hypothesize that the activity state of mTORC1 dynamically regulates local membrane potential by promoting and repressing protein synthesis of select mRNAs. Our hypothesis suggests that mTORC1 uses positive and negative feedback pathways, in a branch-specific manner, to maintain neuronal excitability within an optimal range. In some dendritic branches, mTORC1 activity oscillates between the "On" and "Off" states. We define this as negative feedback. In contrast, positive feedback is defined as the pathway that leads to a prolonged depolarized or hyperpolarized resting membrane potential, whereby mTORC1 activity is constitutively on or off, respectively. We propose that inactivation of mTORC1 increases the expression of voltage-gated potassium alpha (K
1.1 and 1.2) and beta (K
β2) subunits, ensuring that the membrane resets to its resting membrane potential after experiencing increased synaptic activity. In turn, reduced mTORC1 activity increases the protein expression of syntaxin-1A and promotes the surface expression of the ionotropic glutamate receptor N-methyl-D-aspartate (NMDA)-type subunit 1 (GluN1) that facilitates increased calcium entry to turn mTORC1 back on. Under conditions such as learning and memory, mTORC1 activity is required to be high for longer periods of time. Thus, the arm of the pathway that promotes syntaxin-1A and K
1 protein synthesis will be repressed. Moreover, dendritic branches that have low mTORC1 activity with increased K
expression would balance dendrites with constitutively high mTORC1 activity, allowing for the neuron to maintain its overall activity level within an ideal operating range. Finally, such a model suggests that recruitment of more positive feedback dendritic branches within a neuron is likely to lead to neurodegenerative disorders.
Gamma-aminobutyric acid (GABA) is the primary inhibitory neurotransmitter in the central nervous system. In the mature brain, inhibitory GABAergic signaling is critical in maintaining neuronal ...homeostasis and vital human behaviors such as cognition, emotion, and motivation. While classically known to inhibit neuronal function under physiological conditions, previous research indicates a paradoxical switch from inhibitory to excitatory GABAergic signaling that is implicated in several neurological disorders. Various mechanisms have been proposed to contribute to the excitatory switch such as chloride ion dyshomeostasis, alterations in inhibitory receptor expression, and modifications in GABAergic synaptic plasticity. Of note, the hypothesized mechanisms underlying excitatory GABAergic signaling are highlighted in a number of neurodevelopmental, substance use, stress, and neurodegenerative disorders. Herein, we present an updated review discussing the presence of excitatory GABAergic signaling in various neurological disorders, and their potential contributions towards disease pathology.
Little is known about how a neuron undergoes site-specific changes in intrinsic excitability during neuronal activity. We provide evidence for a novel mechanism for mTORC1 kinase-dependent ...translational regulation of the voltage-gated potassium channel Kv1.1 messenger RNA (mRNA). We identified a microRNA, miR-129, that repressed Kv1.1 mRNA translation when mTORC1 was active. When mTORC1 was inactive, we found that the RNA-binding protein, HuD, bound to Kv1.1 mRNA and promoted its translation. Unexpectedly, inhibition of mTORC1 activity did not alter levels of miR-129 and HuD to favor binding to Kv1.1 mRNA. However, reduced mTORC1 signaling caused the degradation of high affinity HuD target mRNAs, freeing HuD to bind Kv1.1 mRNA. Hence, mTORC1 activity regulation of mRNA stability and high affinity HuD-target mRNA degradation mediates the bidirectional expression of dendritic Kv1.1 ion channels.
Dysregulation of biological rhythms plays a role in a wide range of psychiatric disorders. We report mechanistic insights into the rhythms of rapid dopamine signals and cholinergic interneurons ...(CINs) working in concert in the rodent striatum. These rhythms mediate diurnal variation in conditioned responses to reward-associated cues. We report that the dopamine signal-to-noise ratio varies according to the time of day and that phasic signals are magnified during the middle of the dark cycle in rats. We show that CINs provide the mechanism for diurnal variation in rapid dopamine signals by serving as a gain of function to the dopamine signal-to-noise ratio that adjusts across time of day. We also show that conditioned responses to reward-associated cues exhibit diurnal rhythms, with cue-directed behaviors observed exclusively midway through the dark cycle. We conclude that the rapid dopamine signaling rhythm is mediated by a diurnal rhythm in CIN activity, which influences learning and motivated behaviors across the time of day.
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•Dopamine release magnitude exhibits diurnal rhythms•Cholinergic interneuron activity exhibits diurnal rhythms•There is diurnal variation in cholinergic interneuron modulation of dopamine release•Cue-directed conditioned responses are exclusive to rats in their dark cycle
Dopamine signals in the striatum are critical for learning and motivation. Stowe et al. show that diurnal rhythms in rapid dopamine signaling in the striatum are mediated by time-of-day shifts in cholinergic interneuron control of dopamine. These systems work together to mediate time-of-day changes in learning and motivated behaviors.
Abstract Changes in ion channel expression are implicated in the etiology of epilepsy. However, the molecular leading to long-term aberrant expression of ion channels are not well understood. The ...mechanistic/mammalian target of rapamycin (mTOR) is a serine/threonine protein kinase that mediates activity-dependent protein synthesis in neurons. mTOR is overactive in epilepsy, suggesting that excessive protein synthesis may contribute to the neuronal pathology. In contrast, we found that mTOR activity and the microRNA miR-129-5p reduce the expression of the voltage-gated potassium channel Kv1.1 in an animal model of temporal lobe epilepsy (TLE). When mTOR activity is low, Kv1.1 expression is high and the frequency of behavioral seizures is low. However, as behavioral seizure activity rises, mTOR activity increases and Kv1.1 protein levels drop. In CA1 pyramidal neurons, the reduction in Kv1.1 lowers the threshold for action potential firing. Interestingly, blocking mTOR activity with rapamycin reduces behavioral seizures and temporarily keeps Kv1.1 levels elevated. Overtime, seizure activity increases and Kv1.1 protein decreases in all animals, even those treated with rapamycin. Notably, the concentration of miR-129-5p, the negative regulator of Kv1.1 mRNA translation, increases by 21 days post-status epilepticus (SE), sustaining Kv1.1 mRNA translational repression. Our results suggest that following kainic-acid induced status epilepticus there are two phases of Kv1.1 repression: (1) an initial mTOR-dependent repression of Kv1.1 that is followed by (2) a miR-129-5p persistent reduction of Kv1.1.
Mammalian target of rapamycin (mTOR) is implicated in synaptic plasticity and local translation in dendrites. We found that the mTOR inhibitor, rapamycin, increased the Kv1.1 voltage-gated potassium ...channel protein in hippocampal neurons and promoted Kv1.1 surface expression on dendrites without altering its axonal expression. Moreover, endogenous Kv1.1 mRNA was detected in dendrites. Using Kv1.1 fused to the photoconvertible fluorescence protein Kaede as a reporter for local synthesis, we observed Kv1.1 synthesis in dendrites upon inhibition of mTOR or the N-methyl-D-aspartate (NMDA) glutamate receptor. Thus, synaptic excitation may cause local suppression of dendritic Kv1 channels by reducing their local synthesis.
Alcohol use disorder (AUD) differentially impacts men and women and a growing body of evidence points to sex-dependent adaptations in a number of brain regions. In a prior study, we explored the ...effect of a chronic intermittent ethanol exposure (CIE) model of AUD on neuronal and molecular adaptations in the dorsal and ventral domains of the hippocampus (dHC and vHC, respectively) in male rats. We found the vHC to be particularly sensitive to CIE, showing an increase in neuronal excitability and synaptic proteins associated with augmented excitation. These findings were accompanied by a CIE-dependent increase in anxiety-like behaviors. To explore sex-dependent adaptations in the hippocampus, we conducted a similar study in female rats. CIE-treated female rats showed a relatively modest increase in anxiety-like behaviors along with a robust increase in depressive-like measures. Despite both sexes showing clear evidence of a negative affective state following CIE, the vHC of females showed a decrease, rather than an increase, in neuronal excitability. In line with the reduced sensitivity to neural adaptations in the dHC of male rats, we were unable to identify any functional changes in the dHC of females. The functional changes of the vHC in female rats could not be explained by altered expression levels of a number of proteins typically associated with changes in neuronal excitability. Taken together, these findings point to sex as a major factor in CIE-dependent hippocampal adaptations that should be explored further to better understand possible gender differences in the etiology and treatment of AUD.
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