Persistent Stress-Induced Neuroplastic Changes in the Locus Coeruleus/Norepinephrine System

Borodovitsyna, Olga; Joshi, Neal; Chandler, Daniel J.

doi:10.1155/2018/1892570

Cited by 71 publications

(69 citation statements)

References 195 publications

(296 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…As noted above, adults who were exposed to childhood trauma are considerably more vulnerable to experiencing depression and other stress‐related disorders . Considerable evidence from clinical and basic studies suggests that exposure to early life stress is associated with significant neurobiological changes in children and adults, which may underlie the heightened risk of the development of psychiatric disorders and suicidal behaviour .…”

Section: From Research To Practicementioning

confidence: 99%

“…The development of modern neuroscience represents an exceptional prospect to expand contemporary approaches to the study of resilience . Studies suggest that multiple genetic and neurobiological factors play a role in the psychobiology of resilience.…”

Section: State‐of‐the‐art: Resiliencementioning

confidence: 99%

“…Early life stress may result in reduced function of the locus coeruleus–norepinephrine (LC‐NE) system in adulthood . Studies suggest that there is a link between stress, altered LC function, and the pathophysiology of PTSD .…”

Section: State‐of‐the‐art: Resiliencementioning

confidence: 99%

See 2 more Smart Citations

Resilience as a focus of suicide research and prevention

Sher

2019

Acta Psychiatr Scand

132

View full text Add to dashboard Cite

Resilience as a focus of suicide research and prevention Sher L. Resilience as a focus of suicide research and prevention.Suicide is a major medical and social problem. Decades of suicide research have mostly focused on risk factors for suicidal behaviour while overlooking protective factors such as resilience that may help to address this important public health issue. Resilience is the capacity and dynamic process of adaptively overcoming stress and adversity while maintaining normal psychological and physical functioning. Studies conducted over the past 10-15 years suggest that resilience is a protective factor against suicide risk. Resilience is becoming a focus of suicide research and prevention. Building resilience should be a part of universal, selective, and indicated suicide prevention interventions. Promoting resilience may reduce suicide risk in the general population, in groups at elevated suicide risk, and among high-risk individuals. Building resilience in the general population may reduce the incidence of stress-related disorders and, consequently, suicidal behaviour. Improving resilience should be a part of a treatment plan of every psychiatric patient. Mental health professionals will probably have the best success in reducing suicide risk in psychiatric patients if they actively concentrate on increasing stress resilience using both psychosocial and pharmacological interventions. It is critically important to move forward the development of pharmacological and psychological interventions for enhancing resilience.• Mental health professionals should educate the general public regarding issues related to resilience and stress-coping. Promoting resilience in the general population may reduce suicide rates.• Improving resilience may reduce suicide risk among psychiatric patients. Resilience enhancement should be a part of a treatment plan of every psychiatric patient.• Mental health professionals will probably have the best success in reducing suicide risk in psychiatric patients if they actively concentrate on increasing stress resilience using both psychosocial and pharmacological interventions. Limitations• Building resilience is more difficult for some people than for others because some psychobiological factors affecting resilience are not modifiable.• Improving resilience in some cases is difficult because some individuals are very sick and impaired. • Many people around the world who are at elevated suicide risk have a limited or no access to mental health care and to information on resilience and stress-coping.

show abstract

Section: From Research To Practicementioning

confidence: 99%

Section: State‐of‐the‐art: Resiliencementioning

confidence: 99%

See 1 more Smart Citation

Resilience as a focus of suicide research and prevention

Sher

2019

Acta Psychiatr Scand

132

View full text Add to dashboard Cite

show abstract

“…Modern theories of LC function propose that LC activation serves to optimize the trade-off between exploitation and exploration, with strong, global LC activity causing interruption of ongoing activity to enable the selection of appropriate behaviors 20 . Global LC activity is robustly triggered by noxious/stressful stimuli 12,13,24,25,67,78 , which induce anxiety and reduce exploratory activity, through circuits involving the amygdala and prefrontal cortex 3,[13][14][15][16] . Our DREADD-induced activation of the LC similarly reduces exploratory activity and increases anxiety, and globally induces cFos expression throughout the LC.…”

Section: Lc Activation Recapitulates Many Of the Complex Effects Trigmentioning

confidence: 99%

Rapid Reconfiguration of the Functional Connectome after Chemogenetic Locus Coeruleus Activation

Zerbi

Floriou-Servou

Markicevic

et al. 2019

Preprint

107

View full text Add to dashboard Cite

The locus coeruleus (LC) supplies norepinephrine (NE) to the entire forebrain, regulates many fundamental brain functions, and is implicated in several neuropsychiatric diseases. Although selective manipulation of the LC is not possible in humans, studies have suggested that strong LC activation might shift network connectivity to favor salience processing. To test this hypothesis, we use a mouse model to study the impact of LC stimulation on large-scale functional connectivity by combining chemogenetic activation of the LC with resting-state fMRI, an approach we term "chemo-connectomics". LC activation rapidly interrupts ongoing behavior and strongly increases brain-wide connectivity, with the most profound effects in the salience and amygdala networks. We reveal a direct correlation between functional connectivity changes and transcript levels of alpha-1, alpha-2, and beta-1 adrenoceptors across the brain, and a positive correlation between NE turnover and functional connectivity within select brain regions. These results represent the first brain-wide functional connectivity mapping in response to LC activation, and demonstrate a causal link between receptor expression, brain states and functionally connected large-scale networks at rest. We propose that these changes in large-scale network connectivity are critical for optimizing neural processing in the context of increased vigilance and threat detection. RESULTSTo selectively target the LC, we used transgenic mice that express codon-improved Crerecombinase (iCre) under the dopamine-beta-hydroxylase (DBH) promoter (DBH-iCre mice, Figure 1A) 33 . We stereotactically delivered floxed excitatory DREADDs 34 (AAV5-hSyn-DIO-hM3Dq-mCherry; hM3Dq-mCh) or a control virus (AAV5-hSyn-DIO-mCherry; mCh) to the LC, thus restricting virus expression to DBH-positive noradrenergic neurons of the LC (Figure 1B). We assessed successful LC activation using pupillometry, a highly sensitive and clinically relevant readout of LC activation [35][36][37] . After two minutes of baseline recording under light isoflurane anesthesia, we activated LC neurons by administering the potent DREADD activator clozapine at an ultra-low dose (0.03 mg/kg, i.p., Figure 1C) 38 . Within a minute of clozapine injection, we observed a strong increase in pupil diameter in the hM3Dq-mCh group, while pupil diameter of mCh mice did not change in response to clozapine injection and remained stable throughout the 10-minute recording session (Figure 1D-F). To show that our LC activation protocol is behaviorally relevant, we subjected mice to an open field test (OFT) immediately after clozapine injection and recorded their behavior for 30 minutes. In comparison to mCh mice, clozapine injection had profound effects on the behavior of hM3Dq-mCh mice. Several minutes after clozapine administration, hM3Dq-mCh mice showed strongly suppressed locomotor activity ( Figure 1G, H), spent less time in the (more aversive) center of the open field (Figure 1I, J), performed less activity-related supported rears (Figure 1...

show abstract

“…These two neuromodulators also share a neuroanatomical relationship, as galanin is co-expressed with norepinephrine (NE) in a majority of neurons in the locus coeruleus (LC), the primary source of NE in the brain, across species, including mice, rats, monkeys, and humans (4)(5)(6)(7)(8)(9). Most LC research has focused exclusively on NE, despite the fact that galanin has also been independently implicated in stress-induced behaviors in rodents and stress-related neuropsychiatric disorders in humans (10)(11)(12)(13). Stress strongly activates LC neurons, which broadly innervate the rest of the brain and play an important role in regulating attention, arousal, and the fight-or-flight response (14).…”

Section: Introductionmentioning

confidence: 99%

Co-released Norepinephrine and Galanin Act on Different Timescales to Promote Stress-Induced Anxiety-Like Behavior

Tillage

Foster

Lustberg

et al. 2020

Preprint

View full text Add to dashboard Cite

BackgroundBoth the noradrenergic and galaninergic systems have been implicated in stress-related neuropsychiatric disorders, and these two neuromodulators are co-released from the stress-responsive locus coeruleus (LC); however, the individual contributions of LC-derived norepinephrine (NE) and galanin to behavioral stress responses are unclear. Here we aimed to disentangle the functional roles of co-released NE and galanin in stress-induced behavior.MethodsWe used foot shock, optogenetics, and behavioral pharmacology in wild-type (WT) mice and mice lacking either NE (Dbh-/-) or galanin (GalcKO-Dbh) specifically in noradrenergic neurons to isolate the roles of these co-transmitters in regulating anxiety-like behavior in the elevated zero maze (EZM) either immediately or 24 h following stress.ResultsFoot shock and optogenetic LC stimulation produced immediate anxiety-like behavior in WT mice, and the effects of foot shock persisted for 24 h. NE-deficient mice were resistant to the anxiogenic effects of acute stress and optogenetic LC stimulation, while mice lacking noradrenergic-derived galanin displayed typical increases in anxiety-like behavior. However, when tested 24 h after foot shock, both Dbh-/- and GalcKO-Dbh mice lacked normal expression of anxiety-like behavior. Pharmacological rescue of NE, but not galanin, in knockout mice during EZM testing was anxiogenic. In contrast, restoring galanin, but not NE, signaling during foot shock normalized stress-induced anxiety-like behavior 24 h later.ConclusionsThese results indicate that NE and noradrenergic-derived galanin play complementary, but distinguishable roles in behavioral responses to stress. NE is required for the expression of acute stress-induced anxiety, while noradrenergic-derived galanin mediates more persistent responses following a stressor.

show abstract

Persistent Stress-Induced Neuroplastic Changes in the Locus Coeruleus/Norepinephrine System

Cited by 71 publications

References 195 publications

Resilience as a focus of suicide research and prevention

Resilience as a focus of suicide research and prevention

Rapid Reconfiguration of the Functional Connectome after Chemogenetic Locus Coeruleus Activation

Co-released Norepinephrine and Galanin Act on Different Timescales to Promote Stress-Induced Anxiety-Like Behavior

Contact Info

Product

Resources

About