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Neurabin in the anterior cingulate cortex regulates anxiety-like behavior in adult mice.

Kim SS, Wang H, Li XY, Chen T, Mercaldo V, Descalzi G, Wu LJ, Zhuo M - Mol Brain (2011)

Bottom Line: Absence of neurabin, a cytoskeletal protein, resulted in reduced anxiety-like behavior and increased depression-like behavior.Furthermore, loss of neurabin increased the presynaptic release of glutamate and cingulate neuronal excitability.These findings reveal novel roles of the ACC in anxiety disorders, and provide a new therapeutic target for the treatment of anxiety disorders.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Physiology, Faculty of Medicine, University of Toronto Centre for the Study of Pain, ON, Canada.

ABSTRACT
Affective disorders, which include anxiety and depression, are highly prevalent and have overwhelming emotional and physical symptoms. Despite human brain imaging studies, which have implicated the prefrontal cortex including the anterior cingulate cortex (ACC), little is known about the ACC in anxiety disorders. Here we show that the ACC does modulate anxiety-like behavior in adult mice, and have identified a protein that is critical for this modulation. Absence of neurabin, a cytoskeletal protein, resulted in reduced anxiety-like behavior and increased depression-like behavior. Selective inhibition of neurabin in the ACC reproduced the anxiety but not the depression phenotype. Furthermore, loss of neurabin increased the presynaptic release of glutamate and cingulate neuronal excitability. These findings reveal novel roles of the ACC in anxiety disorders, and provide a new therapeutic target for the treatment of anxiety disorders.

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The ACC is critical for anxiety- and depression-like behaviors. A, Model showing the cannulation and microinjection into the ACC. B, Diagram showing the timeline of experiment. C, Percent of time in the open arms of the elevated plus maze. D, Number of entries into the open and closed arms of the elevated plus maze. E, Percent of active mobility in the forced swim test. F, Microinjection sites in the ACC.
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Figure 1: The ACC is critical for anxiety- and depression-like behaviors. A, Model showing the cannulation and microinjection into the ACC. B, Diagram showing the timeline of experiment. C, Percent of time in the open arms of the elevated plus maze. D, Number of entries into the open and closed arms of the elevated plus maze. E, Percent of active mobility in the forced swim test. F, Microinjection sites in the ACC.

Mentions: To determine the role of the ACC in anxiety, we microinjected muscimol, a potent, selective GABAA receptor agonist, into the ACC of C57BL/6 mice, then tested them on the elevated plus maze. Muscimol-injected mice spent significantly more time (Figure 1C; n = 9 for muscimol, n = 6 for saline, * p < 0.05) and made more entries into the open arms (Figure 1D) of the elevated plus maze than the saline-injected mice, suggesting that the ACC was critical for anxiety-like behaviors. There were no differences between groups for closed arm entries (Figure 1D), indicating that the phenotypic differences were not due to hyperactivity. Next, we microinjected into the ACC midazolam, a short-acting benzodiazepine that has potent anxiolytic properties. Similarly to mice microinjected with muscimol, midazolam-injected mice spent significantly more time in the open arms of the elevated plus maze than the saline-injected mice (Figure 2A; n = 6 for midazolam, n = 7 for saline, * p < 0.05), suggesting that injecting a clinically used benzodiazepine into the ACC was sufficient enough to reduce anxiety-like behavior. There were no differences between groups for closed arm entries (Figure 2B). Additionally, since anxiety and depression are often comorbid in patients, we tested for depression-related behavior, as measured by the forced swim test. The forced swim test paradigm reflects the behavioral response to inescapable stress, not conflict, and is sensitive to antidepressant but not anxiolytic treatments [28,29]. Rodents usually struggle to escape from these situations, interspersed with periods of immobility that has been interpreted as "behavioral despair" [30]. When we used the forced swim test to assess mice microinjected with muscimol, we found decreased immobility when compared to the controls (Figure 1E; n = 8 for muscimol, n = 6 for saline, * p < 0.05). The data suggest that the ACC is critical for both anxiety- and depression-like behaviors.


Neurabin in the anterior cingulate cortex regulates anxiety-like behavior in adult mice.

Kim SS, Wang H, Li XY, Chen T, Mercaldo V, Descalzi G, Wu LJ, Zhuo M - Mol Brain (2011)

The ACC is critical for anxiety- and depression-like behaviors. A, Model showing the cannulation and microinjection into the ACC. B, Diagram showing the timeline of experiment. C, Percent of time in the open arms of the elevated plus maze. D, Number of entries into the open and closed arms of the elevated plus maze. E, Percent of active mobility in the forced swim test. F, Microinjection sites in the ACC.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3037880&req=5

Figure 1: The ACC is critical for anxiety- and depression-like behaviors. A, Model showing the cannulation and microinjection into the ACC. B, Diagram showing the timeline of experiment. C, Percent of time in the open arms of the elevated plus maze. D, Number of entries into the open and closed arms of the elevated plus maze. E, Percent of active mobility in the forced swim test. F, Microinjection sites in the ACC.
Mentions: To determine the role of the ACC in anxiety, we microinjected muscimol, a potent, selective GABAA receptor agonist, into the ACC of C57BL/6 mice, then tested them on the elevated plus maze. Muscimol-injected mice spent significantly more time (Figure 1C; n = 9 for muscimol, n = 6 for saline, * p < 0.05) and made more entries into the open arms (Figure 1D) of the elevated plus maze than the saline-injected mice, suggesting that the ACC was critical for anxiety-like behaviors. There were no differences between groups for closed arm entries (Figure 1D), indicating that the phenotypic differences were not due to hyperactivity. Next, we microinjected into the ACC midazolam, a short-acting benzodiazepine that has potent anxiolytic properties. Similarly to mice microinjected with muscimol, midazolam-injected mice spent significantly more time in the open arms of the elevated plus maze than the saline-injected mice (Figure 2A; n = 6 for midazolam, n = 7 for saline, * p < 0.05), suggesting that injecting a clinically used benzodiazepine into the ACC was sufficient enough to reduce anxiety-like behavior. There were no differences between groups for closed arm entries (Figure 2B). Additionally, since anxiety and depression are often comorbid in patients, we tested for depression-related behavior, as measured by the forced swim test. The forced swim test paradigm reflects the behavioral response to inescapable stress, not conflict, and is sensitive to antidepressant but not anxiolytic treatments [28,29]. Rodents usually struggle to escape from these situations, interspersed with periods of immobility that has been interpreted as "behavioral despair" [30]. When we used the forced swim test to assess mice microinjected with muscimol, we found decreased immobility when compared to the controls (Figure 1E; n = 8 for muscimol, n = 6 for saline, * p < 0.05). The data suggest that the ACC is critical for both anxiety- and depression-like behaviors.

Bottom Line: Absence of neurabin, a cytoskeletal protein, resulted in reduced anxiety-like behavior and increased depression-like behavior.Furthermore, loss of neurabin increased the presynaptic release of glutamate and cingulate neuronal excitability.These findings reveal novel roles of the ACC in anxiety disorders, and provide a new therapeutic target for the treatment of anxiety disorders.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Physiology, Faculty of Medicine, University of Toronto Centre for the Study of Pain, ON, Canada.

ABSTRACT
Affective disorders, which include anxiety and depression, are highly prevalent and have overwhelming emotional and physical symptoms. Despite human brain imaging studies, which have implicated the prefrontal cortex including the anterior cingulate cortex (ACC), little is known about the ACC in anxiety disorders. Here we show that the ACC does modulate anxiety-like behavior in adult mice, and have identified a protein that is critical for this modulation. Absence of neurabin, a cytoskeletal protein, resulted in reduced anxiety-like behavior and increased depression-like behavior. Selective inhibition of neurabin in the ACC reproduced the anxiety but not the depression phenotype. Furthermore, loss of neurabin increased the presynaptic release of glutamate and cingulate neuronal excitability. These findings reveal novel roles of the ACC in anxiety disorders, and provide a new therapeutic target for the treatment of anxiety disorders.

Show MeSH
Related in: MedlinePlus