Norepinephrine and dopamine contribute to distinct repetitive behaviors induced by novel odorant stress in male and female mice

Lustberg, Daniel; Liu, Joyce Q.; Iannitelli, Alexa F; Vanderhoof, Samantha O; Liles, L. Cameron; McCann, Katharine E.

doi:10.1016/j.yhbeh.2022.105205

Cited by 13 publications

(18 citation statements)

References 127 publications

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“…The samples were weighed and stored at −80°C until processing for HPLC. As previously described ( Lustberg et al, 2022 ), tissue was thawed on ice and sonicated in 0.1 N perchloric acid (10 μl/mg tissue) for 12 s with 0.5-s pulses. Sonicated samples were centrifuged (16-100 rcf) for 30 min at 4°C, and the supernatant was then centrifuged through 0.45-μm filters at 4000 rcf for 10 min at 4°C.…”

Section: Methodsmentioning

confidence: 99%

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

eNeuro

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The noradrenergic locus coeruleus (LC) is among the earliest sites of tau and α-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 N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (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 (two doses of 50 mg/kg, one 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: Methodsmentioning

confidence: 99%

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

eNeuro

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“…The TMT-induced bedding pushing behavior appears to lack this goal, and in that sense is more related to the burying behavior seen in the marble burying assay. In this assay, a number of glass marbles gets increasingly buried by bedding shoveled by the animal, but this action is considered to be not directed at burying the marbles 58 but rather an undirected expression of anxiety-like behavior 44 . The original goal or benefit of the behavior remains to be determined.…”

Section: Discussionmentioning

confidence: 99%

Cell Type-specific Hypothalamic Pathways to Brainstem Drive Context-dependent Strategies in Response to Stressors

Ahmadlou

Giannouli

Vierbergen

et al. 2023

Preprint

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Selecting the right response to emotional stressors is vital for survival. From the psycho-spatial point of view, the perceived stressors can fall into two conditions: the stressors outside the confined safe zone or inside. Although this novel approach of categorizing the stressors distinguishes two anxiety-associated pathological conditions, agoraphobia, and claustrophobia, the difference between the behavioral responses in these two conditions and the underlying brain circuits are not well understood. Here, using novel behavioral paradigms in mice, we found that outside- and inside-stressors elicit two distinct behaviors, push-bedding and escape-jumping, respectively. Next, in an attempt to identify the brain regions activated in both outside- and inside-stressor conditions, the whole-brain c-Fos staining led us to an unexpected brain region, dorsomedial hypothalamus (DMH). Using optogenetics, chemogenetics, and photometry recording, we discovered that glutamatergic projections from DMH to the periaqueductal gray drive the escape to the inside-stressor, while GABAergic projections, in particular from neurons expressing tachykinin 1, are essential for coping with the outside-stressor. We conclude that distinct populations within the DMH region control the response to psycho-spatially distinct stressors. This discovery shows how the stressors and the spatial information of the stressors integrate in the brain and it is the first to shed light on understanding the narrow border between the two space-associated stress disorders/phobias, i.e. agoraphobia and claustrophobia and the underlying brain mechanisms.

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“…shock) (Bondi et al 2007), psychological threats (e.g. novel environments) (Lustberg et al 2022), and anxiogenic drugs (e.g. cocaine) (Schank et al 2008), while α1AR signaling promotes both exploratory and aversive behaviors in novel environments (Lustberg et al 2020a, Stone et al 2006, Stone et al 1999).…”

Section: Discussionmentioning

confidence: 99%

“…Because no sex differences in stress-induced digging or grooming have been reported in past literature (Dixit et al 2020, Londei et al 1998, Smolinsky AN 2009 or were observed in published experiments from our lab (Lustberg et al 2022) and pilot experiments from this study, male and female mice from the same Dbh genotype were evenly distributed across drug treatment groups, and data were pooled between sexes. All animal procedures and protocols were approved by the Emory University Animal Care and Use Committee, in accordance with the National Institutes of Health guidelines for the care and use of laboratory animals.…”

Section: Animalsmentioning

confidence: 90%

Genetic disruption of dopamine β-hydroxylase dysregulates innate responses to predator odor in mice

Liu

Lustberg

McCann

2023

Preprint

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Rodents infected with the parasite Toxoplasma gondii show reduced aversion to predator odor and diminished neophobia, and infection in humans is associated with increased risk of neuropsychiatric disorders. Norepinephrine (NE) and dopamine (DA) modulate anxiety and predator odor responses, and T. gondii suppresses dopamine β-hydroxylase (Dbh) expression thereby reducing NE and increasing DA, which may contribute to the disruption of innate host behaviors. We examined the consequences of Dbh knockout (Dbh -/-) on responses to predator odor (bobcat urine) and compared them to Dbh-competent littermate controls. Over the first 10 min of predator odor exposure, controls exhibited robust defensive burying behavior, whereas Dbh -/- mice showed high levels of grooming. Defensive burying was potently suppressed in controls by drugs that reduce NE transmission, while excessive grooming in Dbh -/- mice was blocked by DA receptor antagonism. In response to a cotton square scented with a novel neutral odor (lavender), most control mice shredded the material, built a nest, and fell asleep within 90 min. Dbh -/- mice failed to shred the lavender-scented nestlet, but still fell asleep. In contrast, controls sustained high levels of arousal throughout the predator odor test and did not build nests, while Dbh -/- mice were asleep by the 90-min time point, often in shredded bobcat urine-soaked nesting material. Compared with controls exposed to predator odor, Dbh -/- mice demonstrated decreased c-fos induction in the anterior cingulate cortex (ACC), lateral septum (LS), periaqueductal gray (PAG), and bed nucleus of the stria terminalis, but increased c-fos in the LC and medial amygdala. These data indicate that relative ratios of central NE and DA signaling coordinate the type and valence of responses to predator odor, and suggest that Dbh -/- mice may represent a useful monogenetic model of neurobiological changes conferred by T. gondii infection.

show abstract

Norepinephrine and dopamine contribute to distinct repetitive behaviors induced by novel odorant stress in male and female mice

Cited by 13 publications

References 127 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

Cell Type-specific Hypothalamic Pathways to Brainstem Drive Context-dependent Strategies in Response to Stressors

Genetic disruption of dopamine β-hydroxylase dysregulates innate responses to predator odor in mice

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