Central norepinephrine transmission is required for stress-induced repetitive behavior in two rodent models of obsessive-compulsive disorder

Lustberg, Daniel; Iannitelli, Alexa F; Tillage, Rachel P; Pruitt, Molly; Liles, L. Cameron

doi:10.1101/855205

Cited by 11 publications

(26 citation statements)

References 120 publications

(141 reference statements)

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“…Moreover, cognitive impairment is a diagnostic criterion for AD and is common in later stage PD; thus, we assessed the consequences of DSP-4 on LC/NE-sensitive behaviors that reflect prodromal and cognitive abnormalities in AD and PD. We found that lesioned mice were profoundly more reactive in novelty-induced stress paradigms, which are commonly used to model anxiety and are bidirectionally modulated by NE (Lustberg et al, 2020b). DSP-4 treated mice took significantly longer to consume food in the novelty-suppressed feeding test (t(20) = 3.158, p = 0.0048), buried more marbles (t(14) = 4.290, p = 0.0007), and ambulated less during the first hour in a novel cage (t(14) = 2.999, p = 0.0096) compared to saline-treated controls (Fig.…”

Section: Dsp-4 Triggers Loss Of Lc Fibers and Neuroinflammation But N...mentioning

confidence: 86%

The Neurotoxin DSP-4 Dysregulates the Locus Coeruleus-Norepinephrine System and Recapitulates Molecular and Behavioral Aspects of Prodromal Neurodegenerative Disease

Iannitelli

Kelberman

Lustberg

et al. 2022

Preprint

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The noradrenergic locus coeruleus (LC) is among the earliest sites of tau and alpha-synuclein pathology in Alzheimer's disease (AD) and Parkinson's disease (PD), respectively. The onset of these pathologies coincides with loss of noradrenergic fibers in LC target regions and the emergence of prodromal symptoms including sleep disturbances and anxiety. Paradoxically, these prodromal symptoms are indicative of a noradrenergic hyperactivity phenotype, rather than the predicted loss of norepinephrine (NE) transmission following LC damage, suggesting the engagement of complex compensatory mechanisms. Because current therapeutic efforts are targeting early disease, interest in the LC has grown, and it is critical to identify the links between pathology and dysfunction. We employed the LC-specific neurotoxin DSP-4, which preferentially damages LC axons, to model early changes in the LC-NE system pertinent to AD and PD in male and female mice. DSP-4 (2 doses of 50 mg/kg, 1 week apart) induced LC axon degeneration, triggered neuroinflammation and oxidative stress, and reduced tissue NE levels. There was no LC cell death or changes to LC firing, but transcriptomics revealed reduced expression of genes that define noradrenergic identity and other changes relevant to neurodegenerative disease. Despite the dramatic loss of LC fibers, NE turnover and signaling were elevated in terminal regions and were associated with anxiogenic phenotypes in multiple behavioral tests. These results represent a comprehensive analysis of how the LC-NE system responds to axon/terminal damage reminiscent of early AD and PD at the molecular, cellular, systems, and behavioral levels, and provides potential mechanisms underlying prodromal neuropsychiatric symptoms.

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Section: Dsp-4 Triggers Loss Of Lc Fibers and Neuroinflammation But N...mentioning

confidence: 86%

The Neurotoxin DSP-4 Dysregulates the Locus Coeruleus-Norepinephrine System and Recapitulates Molecular and Behavioral Aspects of Prodromal Neurodegenerative Disease

Iannitelli

Kelberman

Lustberg

et al. 2022

Preprint

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“…Patients with major depressive disorder show synaptic deficits and microglial activation associated with severe inflammation in the brain, especially in the anterior cingulate cortex (ACC) (Holmes et al, 2019;Setiawan et al, 2015), a brain region known to modulate responses to stress and emotional outcomes (Barthas et al, 2017;Chana et al, 2003;Ebert and Ebmeier, 1996;Lustberg et al, 2020;Pizzagalli, 2014). In addition, the ACC is known to function in behavioral responses to peripheral inflammation (Miller et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

Early-life inflammation promotes depressive symptoms in adolescence via microglial engulfment of dendritic spines

Cao

Chen

Liu

et al. 2021

Neuron

206

156

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“…The profound lack of anxiety displayed by the Dbh -/-mice in the NSF test contrasts sharply with the seemingly "normal" phenotype of these mice in canonical tests of anxiety, including the elevated plus and zero mazes (EPM/EZM), light/dark box (LDB), and open field test (OFT) (Lustberg et al 2019;Marino et al 2005;Schank et al 2008). These conflict-based models of anxiety-like behavior are widely used in rodent studies, but they rely on the underlying assumption that mice are motivated to explore novel environments (open arms of EPM/EZM, light compartment of LDB, center of OFT).…”

Section: Norepinephrine Is Necessary and Sufficient For Novelty-supprmentioning

confidence: 77%

“…Recently, our group reported hypoactivity in the ACC of NE-deficient mice following cage change stress or exposure to a novel environment containing marbles (Lustberg et al 2019). Unlike control mice, NE-deficient mice demonstrated virtually no stress-induced repetitive behaviors following cage change or novelty exposure, suggesting that NE engagement of the ACC may be necessary for typical affective responses to contextual change (Egner 2011) .…”

Section: Ne-deficient Mice Show Reduced C-fos Induction In Select Tarmentioning

confidence: 98%

“…Although we have clearly demonstrated a critical role for central NE transmission in neophobia, the neurochemistry underlying innate anxiety is complex and likely to involve multiple neuromodulatory systems. Intriguingly, serotonin (5-HT) deficient mice (Tph2 -/-) also exhibit dramatic reductions in neophobia in the NSF test (Angoa-Pérez et al 2012; Mosienko et al 2012).Moreover, these 5-HT deficient mice display increased aggressive and compulsive behaviors, which are absent in NE deficient mice(Angoa-Pérez et al 2012;Lustberg et al 2019;Marino et al 2005;Mosienko et al 2012). Indeed, the phenotypes of Tph2 -/-and Dbh -/-mice are perfectly opposed with the notable exception of reduced neophobia in both mutants, suggesting that behavioral expression of neophobia may require both NE and 5-HT(Blier and El Mansari 2007).…”

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confidence: 99%

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Noradrenergic circuits in the forebrain control affective responses to novelty

Lustberg

Tillage

Bai

et al. 2020

Preprint

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Rationale: In rodents, exposure to novel environments elicits initial anxiety-like behavior (neophobia) followed by intense exploration (neophilia) that gradually subsides as the environment becomes familiar. Thus, innate novelty-induced behaviors are useful indices of anxiety and motivation in animal models of psychiatric disease. Noradrenergic neurons are activated by novelty and implicated in exploratory and anxiety-like responses, but the role of norepinephrine (NE) in neophobia has not been clearly delineated.Objective: We sought to define the role of central NE transmission in neophilic and neophobic behaviors. Methods:We assessed dopamine b-hydroxylase knockout (Dbh -/-) mice lacking NE and their NE-competent (Dbh +/-) littermate controls in neophilic (novelty-induced locomotion; NIL) and neophobic (novelty-suppressed feeding; NSF) behavioral tests with subsequent quantification of brain-wide c-fos induction. We complimented the gene knockout approach with pharmacological interventions.Results: Dbh -/-mice exhibited blunted locomotor responses in the NIL task and completely lacked neophobia in the NSF test. Neophobia was rescued in Dbh -/-mice by acute pharmacological restoration of central NE with the synthetic precursor L-3,4dihydroxyphenylserine (DOPS), and attenuated in control mice by the inhibitory a2-adrenergic autoreceptor agonist guanfacine. Following either NSF or NIL, Dbh -/-mice demonstrated reduced c-fos in the anterior cingulate cortex, medial septum, ventral hippocampus, bed nucleus of the stria terminalis, and basolateral amygdala. Conclusion:These findings indicate that central NE signaling is required for the expression of both neophilic and neophobic behaviors. Further, we describe a putative noradrenergic novelty network as a potential therapeutic target for treating anxiety and substance abuse disorders.

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Central norepinephrine transmission is required for stress-induced repetitive behavior in two rodent models of obsessive-compulsive disorder

Cited by 11 publications

References 120 publications

The Neurotoxin DSP-4 Dysregulates the Locus Coeruleus-Norepinephrine System and Recapitulates Molecular and Behavioral Aspects of Prodromal Neurodegenerative Disease

The Neurotoxin DSP-4 Dysregulates the Locus Coeruleus-Norepinephrine System and Recapitulates Molecular and Behavioral Aspects of Prodromal Neurodegenerative Disease

Early-life inflammation promotes depressive symptoms in adolescence via microglial engulfment of dendritic spines

Noradrenergic circuits in the forebrain control affective responses to novelty

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