Noradrenergic control of cortico-striato-thalamic and mesolimbic cross-structural synchrony.
Although normal dopaminergic tone has been shown to be essential for the induction of cortico-striatal and mesolimbic theta oscillatory activity, the influence of norepinephrine on these brain networks remains relatively unknown. To address this question, we simultaneously recorded local field potentials and single-neuron activity across 10 interconnected brain areas (ventral striatum, frontal association cortex, hippocampus, primary motor cortex, orbital frontal cortex, prelimbic cortex, dorsal lateral striatum, medial dorsal nucleus of thalamus, substantia nigra pars reticularis, and ventral tegmental area) in a combined genetically and pharmacologically induced mouse model of hyponoradrenergia. Our results show that norepinephrine (NE) depletion induces a novel state in male mice characterized by a profound disruption of coherence across multiple cortico-striatal circuits and an increase in mesolimbic cross-structural coherence. Moreover, this brain state is accompanied by a complex behavioral phenotype consisting of transient hyperactivity, stereotypic behaviors, and an acute 12-fold increase in grooming. Notably, treatment with a norepinephrine precursors (l-3,4-dihydroxyphenylalanine at 100 mg/kg or l-threo-dihydroxyphenylserine at 5 mg/kg) or a selective serotonin reuptake inhibitor (fluoxetine at 20 mg/kg) attenuates the abnormal behaviors and selectively reverses the circuit changes observed in NE-depleted mice. Together, our results demonstrate that norepinephrine modulates the dynamic tuning of coherence across cortico-striato-thalamic circuits, and they suggest that changes in coherence across these circuits mediate the abnormal generation of hyperactivity and repetitive behaviors.
Dzirasa
Kafui
K
Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, North Carolina 27710, USA. dzira001@mc.duke.edu
Phillips
H Westley
HW
Sotnikova
Tatyana D
TD
Salahpour
Ali
A
Kumar
Sunil
S
Gainetdinov
Raul R
RR
Caron
Marc G
MG
Nicolelis
Miguel A L
MA
D000200:Action Potentials / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology*; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D003700:Delta Rhythm / Q000187:drug effects; D004295:Dihydroxyphenylalanine / Q000494:pharmacology; D015103:Droxidopa / Q000494:pharmacology; D005473:Fluoxetine / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009434:Neural Pathways / Q000502:physiology*; D009638:Norepinephrine / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000235:genetics; D013826:Theta Rhythm / Q000187:drug effects
D050484:Norepinephrine Plasma Membrane Transport Proteins; D005473:Fluoxetine; D004295:Dihydroxyphenylalanine; D015103:Droxidopa; D009638:Norepinephrine
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