Anatomically and functionally distinct locus coeruleus efferents mediate opposing effects on anxiety-like behavior

Borodovitsyna, Olga; Duffy, Brenna C.; Pickering, Anthony E.; Chandler, Daniel J.

doi:10.1016/j.ynstr.2020.100284

Cited by 44 publications

(38 citation statements)

References 63 publications

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“…The subsets overlap, however. These results are consistent with the newer understanding of LC as containing functionally distinct but intermingled LC ensembles innervating different targets [ 9 , 21 , 22 ]. This spatially more heterogenous LC organization indicates that in addition to any broadcast influences, LC ensembles can support targeted outcome mediation.…”

Section: Introductionsupporting

confidence: 88%

Locus Coeruleus Optogenetic Modulation: Lessons Learned from Temporal Patterns

Harley

Yuan

2021

Brain Sciences

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After reviewing seminal studies using optogenetics to interrogate the functional role of the locus coeruleus in behavior, we conclude that differences in firing rates and firing patterns of locus coeruleus neurons contribute to locus coeruleus nucleus heterogeneity by recruiting different output circuitry, and differentially modifying behavior. The outcomes initiated by different optogenetic input activation patterns and frequencies can have opposite consequences for behavior, activate different neurons in the same target structure, be supported by distinct adrenoceptors and vary with behavioral state.

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Section: Introductionsupporting

confidence: 88%

Locus Coeruleus Optogenetic Modulation: Lessons Learned from Temporal Patterns

Harley

Yuan

2021

Brain Sciences

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“…Rats underwent stessor exposure or control conditions as previously described (Borodovitsyna et al, 2018a(Borodovitsyna et al, , 2020. Briefly, rats were placed in a rodent restrainer (Harvard Apparatus), which was then placed inside of a plastic bell chamber.…”

Section: Stressor Exposurementioning

confidence: 99%

“…We have previously shown that a single acute stressor exposure (15 min combined predator odor and physical restraint) is sufficient to produce behavioral and LC electrophysiological changes a week after stress in adolescent male rats (Borodovitsyna et al, 2018a(Borodovitsyna et al, , 2020. However, this study included only male rats, and it is known that the LC is sexually dimorphic in both morphology and stress responsiveness (Bangasser et al, 2016).…”

Section: Introductionmentioning

confidence: 97%

Age- and Sex-Dependent Changes in Locus Coeruleus Physiology and Anxiety-Like Behavior Following Acute Stressor Exposure

Borodovitsyna

Tkaczynski

Corbett

et al. 2022

Front. Behav. Neurosci.

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Adolescence is a critical period of development with increased sensitivity toward psychological stressors. Many psychiatric conditions emerge during adolescence and animal studies have shown that that acute stress has long-term effects on hypothalamic-pituitary-adrenal axis function and behavior. We recently demonstrated that acute stress produces long-term electrophysiological changes in locus coeruleus and long-lasting anxiety-like behavior in adolescent male rats. Based on prior reports of increased stress sensitivity during adolescence and increased sensitivity of female locus coeruleus toward corticotropin releasing factor, we hypothesized that the same acute stressor would cause different behavioral and physiological responses in adolescent female and adult male and female rats one week after stressor exposure. In this study, we assessed age and sex differences in how an acute psychological stressor affects corticosterone release, anxiety-like behavior, and locus coeruleus physiology at short- and long-term intervals. All groups of animals except adult female responded to stress with elevated corticosterone levels at the acute time point. One week after stressor exposure, adolescent females showed decreased firing of locus coeruleus neurons upon current injection and increased exploratory behavior compared to controls. The results were in direct contrast to changes observed in adolescent males, which showed increased anxiety-like behavior and increased spontaneous and induced firing in locus coeruleus neurons a week after stressor exposure. Adult males and females were both behaviorally and electrophysiologically resilient to the long-term effects of acute stress. Therefore, there may be a normal developmental trajectory for locus coeruleus neurons which promotes stress resilience in adults, but stressor exposure during adolescence perturbs their function. Furthermore, while locus coeruleus neurons are more sensitive to stressor exposure during adolescence, the effect varies between adolescent males and females. These findings suggest that endocrine, behavioral, and physiological responses to stress vary among animals of different age and sex, and therefore these variables should be taken into account when selecting models and designing experiments to investigate the effects of stress. These differences in animals may also allude to age and sex differences in the prevalence of various psychiatric illnesses within the human population.

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“…Other viral strategies have been used to selectively activate noradrenergic LC to spinal cord projections, such as using canine adenoviruses. 6,7,9 This strategy has enabled the selective activation of spinallyprojecting NA neurons in the LC of the rat by expression of pharmacological actuators under the control of the synthetic promoter PRSx8 (9). Therefore, it seems likely that AAV2retro vectors are not ideal for functional studies of descending noradrenergic circuits, whereas alternative retrograde labelling strategies may be better suited.…”

Section: Resistance Of Thþ Neurons To Aav2retro Transductionmentioning

confidence: 99%

Spinally projecting noradrenergic neurons of the locus coeruleus display resistance to AAV2retro-mediated transduction

et al. 2021

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Background The locus coeruleus (LC) is the principal source of noradrenaline (NA) in the central nervous system. Projection neurons in the ventral portion of the LC project to the spinal cord and are considered the main source of spinal NA. To understand the precise physiology of this pathway, it is important to have tools that allow specific genetic access to these descending projections. AAV2retro serotype vectors are a potential tool to transduce these neurons via their axon terminals in the spinal cord, and thereby limit the expression of genetic material to the spinal projections from the LC. Here, we assess the suitability of AAV2retro to target these neurons and investigate strategies to increase their labelling efficiency. Results We show that the neurons in the LC that project to the spinal dorsal horn are largely resistant to transduction with AAV2retro serotype vectors. Compared to Cholera toxin B (CTb) tracing, AAV2retro.eGFP labelled far fewer neurons within the LC and surrounding regions, particularly within neurons that express tyrosine hydroxylase (TH), the rate-limiting enzyme for NA synthesis. We also show that the sensitivity for transduction of this projection can be increased using AAV2retro.eGFP.cre in ROSA26tdTom reporter mice (23% increase), with a higher proportion of the newly revealed neurons expressing TH compared to those directly labelled with AAV2retro containing an eGFP expression sequence. Conclusion These tracing studies identify limitations in AAV2retro-mediated retrograde transduction of a subset of projection neurons, specifically those that express NA and project to the spinal cord. This is likely to have implications for the study of NA-containing projections as well as other types of projection neuron in the central nervous system.

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Anatomically and functionally distinct locus coeruleus efferents mediate opposing effects on anxiety-like behavior

Cited by 44 publications

References 63 publications

Locus Coeruleus Optogenetic Modulation: Lessons Learned from Temporal Patterns

Locus Coeruleus Optogenetic Modulation: Lessons Learned from Temporal Patterns

Age- and Sex-Dependent Changes in Locus Coeruleus Physiology and Anxiety-Like Behavior Following Acute Stressor Exposure

Spinally projecting noradrenergic neurons of the locus coeruleus display resistance to AAV2retro-mediated transduction

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