Chronic Stress Causes Amygdala Hyperexcitability in Rodents

Abstract

Background-Chronic stress is a major health concern, often leading to depression, anxiety or when severe enough, post-traumatic stress disorder (PTSD). While many studies demonstrate that the amygdala is hyper-responsive in patients with these disorders, the cellular neurophysiological effects of chronic stress on the systems that underlie psychiatric disorders, such as the amygdala, are relatively unknown.

Effects of Repeated Stress on Age-Dependent GABAergic Regulation of the Lateral Nucleus of the Amygdala

“…For instance, increased excitatory responses to glutamate and increased glutamatergic synaptic transmission. The increased excitatory response to glutamate could be caused by increased neuronal membrane excitability (Rosenkranz et al, 2010;Hetzel and Rosenkranz, 2014), increased function of NMDA or AMPA receptors (Adamec et al, 2005;Caudal et al, 2010;Mozhui et al, 2010;Suvrathan et al, 2014), reduced glutamatergic drive of GABAergic networks (Masneuf et al, 2014), or upregulation of glutamatergic receptors (Lei and Tejani-Butt, 2010;Gan et al, 2014). Increased glutamatergic synaptic transmission could be caused by increased glutamatergic inputs, as observed here and in other studies (Mitra et al, 2005;Vyas et al, 2006;Padival et al, 2013Padival et al, , 2015Suvrathan et al, 2014;Tsai et al, 2014).…”

“…Studies have repeatedly demonstrated that the increased activity of the amygdala in adult male rats after stress parallels increased anxiety (Vyas et al, 2004;DoremusFitzwater et al, 2009;Rosenkranz et al, 2010) and production of behaviors that rely on the BLA, such as such as freezing in response to a fear-conditioned cue (Conrad et al, 1999;Rau et al, 2005;Rodriguez Manzanares et al, 2005;ToledoRodriguez and Sandi, 2007;Atchley et al, 2012;Zhang and Rosenkranz, 2013). Relatively less is known about the effects of stress on amygdala-dependent behaviors in adolescents; however, in several studies increased fear conditioning is accompanied by an impairment of fear extinction in adolescents and enhanced generalization of fear (Morrissey et al, 2011;Zhang and Rosenkranz, 2013;Muller et al, 2014;Padival et al, 2015).…”

“…This specific design reduces habituation to restraint, which would otherwise be significant (Zhang et al, 2014). Previous behavioral and electrophysiological studies demonstrate that this is an effective protocol to induce changes in BLA-dependent behaviors and BLA neuronal firing (Rosenkranz et al, 2010;Atchley et al, 2012;Rosenkranz, 2012, 2013). Three different sizes of restraint hemicylinders were used to fit the size of the rats such that movement of the body was similarly restricted in adult and adolescent rats.…”

“…Rats in the repeated restraint group were placed into a hemicylinder restraint tube for 20 min per session and 1 session per day for 7 out of 9 days in a procedure room (Rosenkranz et al, 2010;Rosenkranz, 2012, 2013). This specific design reduces habituation to restraint, which would otherwise be significant (Zhang et al, 2014).…”

Biological Alterations in Depression

“…Given the functional roles of specific brain regions in emotional processing, neuropathological abnormalities observed in depression suggest that areas that mediate autonomic and neuroendocrine responses (amygdala) is associated with increased activity and cerebral blood flow, while reduction in activity is observed in brain regions that control emotional processing (cortex) (Manji et al, 2001). Antidepressant treatment reduces CBF and metabolism in the amygadala (Drevets, 2000b;Drevets et al, 1999), attenuating hyperresponsiveness to stress (Rosenkranz et al, 2010). Similarly, larger hippocampal volume (Frodl et al, 2008;Kronmuller et al, 2008;MacQueen et al, 2008) and gray matter density in the ACC (Costafreda et al, 2009) were positively correlated with antidepressant response.…”