Lithium Ameliorates Nucleus Accumbens Phase-Signaling Dysfunction in a Genetic Mouse Model of Mania

Dzirasa, Kafui; Coque, Laurent; Sidor, Michelle M.; Kumar, Sunil; Dancy, Elizabeth A.; Takahashi, Joseph S.; McClung, Colleen A.; Nicolelis, Miguel A. L.

doi:10.1523/jneurosci.4289-10.2010

Cited by 74 publications

(72 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The most thorough examination of this frequency band in the behaving rodent may be that of Fujisawa and Buzsáki (2011), who found that coherence between 2 and 5 Hz increased between the ventral tegmental area (VTA) and prelimbic cortex during an odor-to-place matching task, and that this oscillation was phase-coupled with theta in the dorsal hippocampus. This report extended previous observations that VTA neurons often fire action potentials at regular intervals of 4 Hz (Hyland et al, 2002;Paladini and Tepper, 1999;Bayer et al, 2007;Dzirasa et al, 2010;Kobayashi and Schultz, 2008). Hippocampal-prefrontal coherence in the 4 Hz band can also increase when dopamine is injection directly into the prefrontal cortex (Benchenane et al, 2010).…”

Section: Discussionsupporting

confidence: 88%

Chronic deep brain stimulation of the rat ventral medial prefrontal cortex disrupts hippocampal–prefrontal coherence

Insel

Pilkiw

Nóbrega

et al. 2015

Experimental Neurology

View full text Add to dashboard Cite

Deep brain stimulation (DBS) of the subgenual cingulate gyrus (SCG) has been used to treat patients with treatment-resistant depression. As in humans, DBS applied to the ventromedial prefrontal cortex of rats induces antidepressant-like responses. Physiological interactions between structures that play a role in depression and antidepressant treatment are still unknown. The present study examined the effect of DBS on inter-region communication by measuring the coherence of local field potentials in the rat infralimbic cortex (IL; homologue of the SCG) and one of its major afferents, the ventral hippocampus (VH). Rats received daily IL DBS treatment (100 μA, 90 μs, 130 Hz; 8 h/day). Recordings were conducted in unrestrained, behaving animals on the day before treatment, after 1 and 10 days of treatment, and 10 days stimulation offset. VH-IL coherence in the 2-4 Hz range was reduced in DBS-treated animals compared with shams after 10 days, but not after only 1 day of treatment. No effect of DBS was observed in the 6-10 Hz (theta) range, where coherence was generally high and could be further evoked with a loud auditory stimulus. Finally, coherence was not affected by fluoxetine (10 mg/kg), suggesting that the effects of DBS were not likely mediated by increased serotonin levels. While these data support the hypothesis that DBS disrupts communication between regions important for expectation-based control of emotion, they also suggest that lasting physiological effects require many days of treatment and, furthermore, may be specific to lower-frequency patterns, the nature and scope of which await further investigation.☆ NI, MP and CH designed the experiments; NI and MP performed the experiments; NI analyzed the data; NI, JN, WDH, KT, and CH wrote the paper.

show abstract

Section: Discussionsupporting

confidence: 88%

Chronic deep brain stimulation of the rat ventral medial prefrontal cortex disrupts hippocampal–prefrontal coherence

Insel

Pilkiw

Nóbrega

et al. 2015

Experimental Neurology

View full text Add to dashboard Cite

show abstract

“…What is clear from all of these studies is that anxiety-related behavior and depressionrelated behavior are regulated by separate mechanisms. Recently, we found that the ClockD19 mice have a defect in the phasic entrainment of d and g oscillations in the NAc neurons, which can be rescued by chronic lithium treatment (Dzirasa et al, 2010). It is very likely that it is not merely the increase or decrease in firing rates within the VTA-NAc circuit that is important in regulating mood, but the patterns of firing, oscillations, and coherence between and within structures is what dictates the behavioral-and moodrelated outputs.…”

Section: Discussionmentioning

confidence: 99%

Specific Role of VTA Dopamine Neuronal Firing Rates and Morphology in the Reversal of Anxiety-Related, but not Depression-Related Behavior in the ClockΔ19 Mouse Model of Mania

Coque

Mukherjee

Cao

et al. 2011

Neuropsychopharmacol

111

100

View full text Add to dashboard Cite

Lithium has been used extensively for mood stabilization, and it is particularly efficacious in the treatment of bipolar mania. Like other drugs used in the treatment of psychiatric diseases, it has little effect on the mood of healthy individuals. Our previous studies found that mice with a mutation in the Clock gene (ClockD19) have a complete behavioral profile that is very similar to human mania, which can be reversed with chronic lithium treatment. However, the cellular and physiological effects that underlie its targeted therapeutic efficacy remain unknown. Here we find that ClockD19 mice have an increase in dopaminergic activity in the ventral tegmental area (VTA), and that lithium treatment selectively reduces the firing rate in the mutant mice with no effect on activity in wild-type mice. Furthermore, lithium treatment reduces nucleus accumbens (NAc) dopamine levels selectively in the mutant mice. The increased dopaminergic activity in the Clock mutants is associated with cell volume changes in dopamine neurons, which are also rescued by lithium treatment. To determine the role of dopaminergic activity and morphological changes in dopamine neurons in manic-like behavior, we manipulated the excitability of these neurons by overexpressing an inwardly rectifying potassium channel subunit (Kir2.1) selectively in the VTA of ClockD19 mice and wild-type mice using viral-mediated gene transfer. Introduction of this channel mimics the effects of lithium treatment on the firing rate of dopamine neurons in ClockD19 mice and leads to a similar change in dopamine cell volume. Furthermore, reduction of dopaminergic firing rates in ClockD19 animals results in a normalization of locomotor-and anxiety-related behavior that is very similar to lithium treatment; however, it is not sufficient to reverse depression-related behavior. These results suggest that abnormalities in dopamine cell firing and associated morphology underlie alterations in anxiety-related behavior in bipolar mania, and that the therapeutic effects of lithium come from a reversal of these abnormal phenotypes.

show abstract

“…More recently, growing evidence has raised the possibility of striatal dysfunction associated with ADHD and autism (Durston et al 2003;Lou et al 2004;Di Martino et al 2011;Peca et al 2011). Interestingly, a notable number of mouse models for neuropsychiatric disorders share a common phenotype of elevated locomotor activity (Bolivar et al 2004;Welch et al 2007;Dzirasa et al 2010;Penagarikano et al 2011;Won et al 2012). A study in mice deficient of contactin associated protein-like 2 (CNTNAP2) reported that hyperactivity and perseveration could be rescued by risperidone, a dopamine D 2 receptor agonist, while social deficits remained impaired.…”

Section: The Modulation Of Excitatory and Inhibitory Balance In Locommentioning

confidence: 99%

Functional roles of neurotransmitters and neuromodulators in the dorsal striatum

Kim

Bakes

et al. 2012

Learn. Mem.

View full text Add to dashboard Cite

The dorsal striatum, with its functional microcircuits galore, serves as the primary gateway of the basal ganglia and is known to play a key role in implicit learning. Initially, excitatory inputs from the cortex and thalamus arrive on the direct and indirect pathways, where the precise flow of information is then regulated by local GABAergic interneurons. The balance of excitatory and inhibitory transmission in the dorsal striatum is modulated by neuromodulators such as dopamine and acetylcholine. Under pathophysiological states in the dorsal striatum, an alteration in excitatory and inhibitory transmission may underlie dysfunctional motor control. Here, we review the cellular connections and modulation of striatal microcircuits and propose that modulating the excitatory and inhibitory balance in synaptic transmission of the dorsal striatum is important for regulating locomotion.The dorsal striatum is best known for its role in decision-making, especially in action selection and initiation through the convergence of sensorimotor, cognitive, and motivational information (DeLong 1990;Smith et al. 1998;Balleine et al. 2007). As the primary input of the basal ganglia, the striatum receives glutamatergic inputs from the cortex and thalamus and in turn projects GABAergic outputs to the globus pallidus and substantia nigra pars reticulata (SNr). Inputs from the cortex and thalamus both form excitatory synaptic connections on medium spiny neurons (MSN) in which cortical afferents are from the sensory, motor, and associational cortex (Bolam et al. 2000), and thalamic afferents are from the intralaminar thalamic nuclei (Doig et al. 2010). These glutamatergic inputs are then processed in the dorsal striatum where numerous connections between various types of neurons exist. Thus, the complexity of neuronal circuits has made it difficult to elucidate the functional roles of the striatum. Recently, studies focused on interneurons that reside in the dorsal striatum have characterized the physiological features and functional connections. For example, parvalbumin-expressing fastspiking interneurons (PV-FSI) and neuropeptide-Y positive lowthreshold spiking interneurons (NPY-LTS) form synaptic connections with MSNs and regulate the firing activity of the principal neuron MSNs (Koos and Tepper 1999;Gittis et al. 2010;Chuhma et al. 2011). These interneurons were shown to have distinct firing patterns and connections, and thus they may exert different effects on MSNs. Other crucial connections are the cholinergic, dopaminergic, and serotonergic axons that strongly innervate the dorsal striatum. These projections are essential for modulating striatal circuits and disruption of such signaling can result in movement impairments and neurological disorders such as Huntington's disease (Lovinger 2010). This review summarizes recent reports of the microcircuits present in the dorsal striatum, although serotonergic signaling is excluded, and suggests a putative role for striatal microcircuits in motor dysfunction and/or hyperactivity that ...

show abstract

Lithium Ameliorates Nucleus Accumbens Phase-Signaling Dysfunction in a Genetic Mouse Model of Mania

Cited by 74 publications

References 44 publications

Chronic deep brain stimulation of the rat ventral medial prefrontal cortex disrupts hippocampal–prefrontal coherence

Chronic deep brain stimulation of the rat ventral medial prefrontal cortex disrupts hippocampal–prefrontal coherence

Specific Role of VTA Dopamine Neuronal Firing Rates and Morphology in the Reversal of Anxiety-Related, but not Depression-Related Behavior in the ClockΔ19 Mouse Model of Mania

Functional roles of neurotransmitters and neuromodulators in the dorsal striatum

Contact Info

Product

Resources

About