Neonatal isolation augments social dominance by altering actin dynamics in the medial prefrontal cortex

Abstract

Social separation early in life can lead to the development of impaired interpersonal relationships and profound social disorders. However, the underlying cellular and molecular mechanisms involved are largely unknown. Here, we found that isolation of neonatal rats induced glucocorticoid-dependent social dominance over nonisolated control rats in juveniles from the same litter. Furthermore, neonatal isolation inactivated the actin-depolymerizing factor (ADF)/cofilin in the juvenile medial prefrontal cortex (mPFC). Isolation-induced inactivation of ADF/cofilin increased stable actin fractions at dendritic spines in the juvenile mPFC, decreasing glutamate synaptic AMPA receptors. Expression of constitutively active ADF/cofilin in the mPFC rescued the effect of isolation on social dominance. Thus, neonatal isolation affects spines in the mPFC by reducing actin dynamics, leading to altered social behavior later in life.medial prefrontal cortex | social isolation stress | social dominance | AMPA receptor trafficking | actin dynamics

Disruption of behavior and brain metabolism in artificially reared rats

“…Neural activity, neurotransmitter release, and growth factors are also disrupted during social isolation in rats before or after weaning (Cirulli et al, 2003;Chatterjee et al, 2007;Le on-Rodr ıguez and Dueñas, 2013;Toda et al, 2014;Wang et al, 2015), and these alterations associate with glial underdevelopments. The main structures affected are amygdala (Fleming et al, 1994;Sanchez et al, 1995;Lyons et al, 2010;Lukkes et al, 2012;Toda et al, 2014;Padival et al, 2015), the medial prefrontal cortex (Silva-G omez et al, 2003;Braun et al, 2009;Miyazaki et al, 2012;Wall et al, 2012;Tada et al, 2016), hippocampus (Silva-G omez et al, 2003;Bonab et al, 2012;Wang and Gondr e-Lewis, 2013), and the HPA axis (Akbari et al, 2008;Daniels et al, 2009;Vargas et al, 2016).…”

New insights into early-life stress and behavioral outcomes

“…Much research employing animal models has focused on hippocampus-dependent memory, because of the availability of standardized tests and well-characterized neural substrates, molecules and mechanisms. We describe some of these findings, and regret that space limitations prevent us from discussing executive functions and other prefrontal cortex-dependent behaviors in the context of early-life stress [66–68]. …”

Peptide regulation of cofilin activity in the CNS: A novel therapeutic approach for treatment of multiple neurological disorders

“…Cofilin phosphoregulation is significantly shifted from the norm in rodent models of many neurological disorders, including AD (Zhao et al, 2006; Woo et al, 2015a; Woo et al, 2015b), autism (Duffney et al, 2015; Liu et al, 2016), manic/bipolar disorder (Lee et al, 2016), sleep deprivation (Havekes et al, 2016), neonatal isolation (Tada et al, 2016), and neuropathic pain (Qiu et al, 2016) (Table 1). Dendritic spine shrinkage occurs as a result of cofilin hyperactivation (dephosphorylation) and has been observed in hippocampal neurons during establishment of long-term depression (Figure 2; Zhou et al, 2004), and in neurons of the hippocampus but not the prefrontal cortex of sleep deprived mice (Havekes et al, 2016).…”

“…Dendritic spine shrinkage occurs as a result of cofilin hyperactivation (dephosphorylation) and has been observed in hippocampal neurons during establishment of long-term depression (Figure 2; Zhou et al, 2004), and in neurons of the hippocampus but not the prefrontal cortex of sleep deprived mice (Havekes et al, 2016). Neonatal rats subjected to social isolation exhibit increased aggression as juveniles, and this correlates with increased cofilin phosphorylation in the prefrontal cortex (Tada et al, 2016). Together, these findings demonstrate that cofilin activity within different CNS neuronal populations is uniquely responsive to the specific input.…”

“…Similarly, the aggressive tendencies of neonatally-isolated rats can be corrected by modulating cofilin activity through virus-mediated local expression of full-length cofilin. In this case, hyperphosphorylation (reduced activity) of cofilin is counteracted by expression of constitutively active cofilin S3A (Tada et al, 2016). Although this approach is not peptide therapy per se , it suggests that local synthesis of cofilin activity-modulating peptides (such as S3 or a pS3 mimetic form such as S3D) within neuronal sub-populations might be applicable to a wide variety of neuro-behavioral issues.…”