Chronic Inactivation of the Orbitofrontal Cortex Increases Anxiety-Like Behavior and Impulsive Aggression, but Decreases Depression-Like Behavior in Rats

Abstract

The orbitofrontal cortex (OFC) is involved in emotional processing, and orbitofrontal abnormalities have often been observed in various affective disorders. Thus, chronic dysfunction of the OFC may cause symptoms of affective disorders, such as anxiety, depression and impulsivity. Previous studies have investigated the effect of orbitofrontal dysfunction on anxiety-like behavior and impulsive aggression in rodents, but the results are inconsistent possibly reflecting different methods of OFC inactivation. These studies used either a lesion of the OFC, which may affect other brain regions, or a transient inactivation of the OFC, whose effect may be restored in time and not reflect effects of chronic OFC dysfunction. In addition, there has been no study on the effect of orbitofrontal inactivation on depression-like behavior in rodents. Therefore, the present study examined whether chronic inactivation of the OFC by continuous infusion of a GABAA receptor agonist, muscimol, causes behavioral abnormalities in rats. Muscimol infusion inactivated the ventral and lateral part of the OFC. Following a week of OFC inactivation, the animals showed an increase in anxiety-like behavior in the open field test and light-dark test. Impulsive aggression was also augmented in the chronically OFC-inactivated animals because they showed increased frequency of fighting behavior induced by electric foot shock. On the other hand, chronic OFC inactivation reduced depression-like behavior as evaluated by the forced swim test. Additionally, it did not cause a significant change in corticosterone secretion in response to restraint stress. These data suggest that orbitofrontal neural activity is involved in the regulation of anxiety- and depression-like behaviors and impulsive aggression in rodents.

Neural bases of Frustration-Aggression Theory: A multi-domain meta-analysis of functional neuroimaging studies

“…Furthermore, lesions (or inactivation) of the OFC/vmPFC are frequently linked with greater emotional reactivity and impulsive aggression (Agustín-Pavón et al, 2012; Berlin, Rolls, & Kischka, 2004; H. A. Berlin, Rolls, & Iversen, 2005; Izquierdo, Suda, & Murray, 2005; Kuniishi et al, 2017; Shiba et al, 2015) likely through a disrupted connectivity with the amygdala (Motzkin, Philippi, Wolf, Baskaya, & Koenigs, 2015). Indeed, evidence strongly support the role of deficient vmPFC-amygdala connectivity as a main neurobiological marker of individuals at risk for aggression (Blair, 2008; Blair, 2016; Blair, 2007; Marsh et al, 2011; Marsh et al, 2008; Yoder, Harenski, Kiehl, & Decety, 2015).…”

“…Furthermore, lesions (or inactivation) of the OFC/vmPFC are frequently linked with greater emotional reactivity and impulsive aggression (Agustín-Pavón et al, 2012;Berlin, Rolls, & Kischka, 2004;H. A. Berlin, Rolls, & Iversen, 2005;Izquierdo, Suda, & Murray, 2005;Kuniishi et al, 2017;Shiba et al, 2015) likely through a disrupted connectivity with the amygdala (Motzkin, Philippi, Wolf, Baskaya, & Koenigs, 2015).…”

The Dorsal Raphe Regulates the Duration of Attack through the Medial Orbitofrontal Cortex and Medial Amygdala

“…The MeOC and MeA are subregions densely innervated areas by the DR ( Cádiz-Moretti et al, 2016 ; Murphy and Deutch, 2018 ; Ren et al, 2018 ) and are key nodes in the processing of social interaction including aggression ( Blair, 2004 ; Siever, 2008 ; Rosell et al, 2010 ; Hong et al, 2014 ; Rosell and Siever, 2015 ; Unger et al, 2015 ; Buades-Rotger et al, 2017 ; Haller, 2018 ). Activity within the OFC is negatively correlated with aggression and chronic inactivation or lesioning in this area heightens aggression in mice and humans ( Anderson et al, 1999 ; Blair, 2004 ; Siever, 2008 ; Rosell et al, 2010 ; Beyer et al, 2015 ; Rosell and Siever, 2015 ; Kuniishi et al, 2016 ). The role of the MeA in aggression is better characterized.…”

Aberrant Gray Matter Volume and Cortical Surface in Paranoid-Type Delusional Disorder

“…It is noteworthy that OFC volume increase could be observed after long-term antipsychotic treatment [67]. Also, regulation of amygdala activity by OFC during threat-related anxiety has been well-described by previous research [65,[68][69][70], so that higher GMV in this region may reflect treatment effects. Finally, non-pharmacologic structural remodeling processes may account for increased OFC volume as well [71].…”