Targeted ablation of cholinergic interneurons in the dorsolateral striatum produces behavioral manifestations of Tourette syndrome

Xu, Meiyu; Kobets, Andrew J.; Du, Jung‐Chieh; Lennington, Jessica B.; Li, Lina; Banasr, Mounira; Duman, Ronald S.; Vaccarino, Flora M.; DiLeone, Ralph J.; Pittenger, Christopher

doi:10.1073/pnas.1419533112

Cited by 145 publications

(188 citation statements)

References 61 publications

Supporting

Mentioning

164

Contrasting

Order By: Relevance

“…1E,F). Previous studies have used selective expression of DTR as a method for killing populations of neurons defined by their neurochemical phenotype or spatial location (Gropp et al, 2005;Carter et al, 2013;Xu et al, 2015). Our methodology expands on previous techniques to ablate neurons in a structure that project to a distinct target site, thereby killing these neurons in a directionally specific manner.…”

Section: Discussionmentioning

confidence: 99%

Regulation of Alcohol Extinction and Cue-Induced Reinstatement by Specific Projections among Medial Prefrontal Cortex, Nucleus Accumbens, and Basolateral Amygdala

Keistler¹,

Hammarlund²,

Barker

et al. 2017

J. Neurosci.

Self Cite

View full text Add to dashboard Cite

The ability to inhibit drinking is a significant challenge for recovering alcoholics, especially in the presence of alcohol-associated cues. Previous studies have demonstrated that the regulation of cue-guided alcohol seeking is mediated by the basolateral amygdala (BLA), nucleus accumbens (NAc), and medial prefrontal cortex (mPFC). However, given the high interconnectivity between these structures, it is unclear how mPFC projections to each subcortical structure, as well as projections between BLA and NAc, mediate alcohol-seeking behaviors. Here, we evaluate how cortico-striatal, cortico-amygdalar, and amygdalo-striatal projections control extinction and relapse in a rat model of alcohol seeking. Specifically, we used a combinatorial viral technique to express diphtheria toxin receptors in specific neuron populations based on their projection targets. We then used this strategy to create directionally selective ablations of three distinct pathways after acquisition of ethanol self-administration but before extinction and reinstatement. We demonstrate that ablation of mPFC neurons projecting to NAc, but not BLA, blocks cue-induced reinstatement of alcohol seeking and neither pathway is necessary for extinction of responding. Further, we show that ablating BLA neurons that project to NAc disrupts extinction of alcohol approach behaviors and attenuates reinstatement. Together, these data provide evidence that the mPFC¡NAc pathway is necessary for cueinduced reinstatement of alcohol seeking, expand our understanding of how the BLA¡NAc pathway regulates alcohol behavior, and introduce a new methodology for the manipulation of target-specific neural projections.

show abstract

Section: Discussionmentioning

confidence: 99%

Regulation of Alcohol Extinction and Cue-Induced Reinstatement by Specific Projections among Medial Prefrontal Cortex, Nucleus Accumbens, and Basolateral Amygdala

Keistler¹,

Hammarlund²,

Barker

et al. 2017

J. Neurosci.

Self Cite

View full text Add to dashboard Cite

show abstract

“…Postmortem studies have shown a decrease in choline acetyltransferase containing striatal interneurons, supporting reports of an anatomical reduction of cholinergic interneurons 15 . In mice, ablation of 50% of cholinergic interneurons in the dorsomedial striatum caused no effect, whereas ablation in the dorsolateral striatum plus a stressful stimuli or amphetamine challenge caused tic-like stereotypic behaviours 29 . Striatal cholinergic interneurons may coopt dopamine terminals and drive GABA release 30 .…”

Section: Acetylcholinementioning

confidence: 98%

Gilles de la Tourette syndrome

Robertson

Eapen

Singer

et al. 2017

Nat Rev Dis Primers

285

244

View full text Add to dashboard Cite

The unstructured abstract of 200 words maximum should summarize the main points of the article. All information mentioned in the abstract must be addressed somewhere in the main article. The abstract should not contain references or display item citations. Gilles de la Tourette Syndrome (GTS), a reasonably common disorder, has had a long, tortuous and somewhat controversial history. First and well described in the 18th century 1,2 , the main features of GTS have, however, remained fairly constant. The core diagnostic features are multiple motor and one or more vocal (phonic) tics lasting for over a year. In addition, almost pathognomic, but not necessary, features described in the early documentations include coprolalia (involuntary, inappropriate swearing), and echophenomena (copying behaviours), as well as many co-morbidities and psychopathologies 3 . Introduction [suggested 500 words, is 544 words -8 refs] Mary Robertson Thoughts for Mary -Your word count when combining sections 1 and 2 is 1001 (1000 limit)-so OKGTS was originally described in France and the majority of early literature came from and standardised schedules such as diagnostic confidence, measurement of severity, QoL, and assessment of both co-morbidities and co-existent psychopathologies are currently available.Large international collaborative consortia are engaged in studies exploring aetiological factors in particular, and some international treatment studies are also underway. Perhaps as a result of earlier small patient numbers, the treatment trials have given good clues to management, but unsurprisingly systematic reviews and meta-analyses have been hampered, giving disappointing, if not unexpected, results. Intriguingly medications from the typical NRDP -Gilles de la Tourette Syndrome 3 antipsychotic family including haloperidol, which first had documented success in 1961 6,7 are still being used, although successive generations of "atypicals" are currently more in vogue,as are medications such as alpha-2-adrenergic agonists. Interestingly, haloperidol remains the only medication prescribed on licence in many parts of the world. In contrast to disorders such as ADHD, in which it is clear which treatments work and which do not require further study 8 , a variety of treatment studies in GTS are still being undertaken, including using other medications (trying to improve efficacy and reduce side effects), behavioural therapies, deep brain stimulation (for refractory cases), and other more "alternative" methods such as "orthotics" (teeth braces). The GTS community has to first agree on how common GTS is and then seek funding for research in the areas of major importance.2. Epidemiology [suggested 500 words, is 444 words, 6 additional refs] Mary Robertson GTS was for many years thought to be not only very rare, but a bizarre curiosity, with sporadic case reports peppering the literature. The belief that GTS was uncommon at the very least was held by many until Comings 9 controversially suggested that GTS occurred in between 0.66% and...

show abstract

“…At the November, 2014, annual meeting of the Society for Neuroscience, Xu et al presented evidence that removing about half of the cholinergic interneurons in the dorsolateral striatum reproduced some features of TS in a rodent model 9 ; see also 10 . This model was inspired by the fascinating autopsy studies that found decreased numbers of striatal interneurons in Tourette syndrome 11 .…”

Section: Resultsmentioning

confidence: 99%