Early life programming of hemispheric lateralization and synchronization in the adult medial prefrontal cortex

Abstract

Abstract-Neonatal maternal separation (MS) in the rat increases the vulnerability to stressors later in life. In contrast, brief handling (H) in early life confers resilience to stressors in adulthood. Early life programming of stress reactivity may involve the medial prefrontal cortex (mPFC), a region which modulates various stress responses. Moreover, hemispheric specialization in mPFC may mediate adaptive coping responses to stress. In the present study, neuronal activity was examined simultaneously in left and right mPFC in adult rats previously subjected to MS, H or animal facility rearing (AFR). In vivo electrophysiology, under isoflurane anesthesia, was used to conduct acute recordings of unit and local field potential (LFP) activity in response to systemic administration of N-methyl-␤-carboline-3-carboxamide (FG-7142), a benzodiazepine receptor partial inverse agonist which mimics various stress responses. MS decreased basal unit activity selectively in right mPFC. Basal LFP activity was reduced with MS in left and right mPFC, compared to AFR and H, respectively. Hemispheric synchronization of basal LFP activity was also attenuated by MS at lower frequencies. FG-7142 elicited lateralized effects on mPFC activity with different early rearing conditions. Activity in left mPFC was greater with AFR and MS (AFR>MS), whereas activity was predominantly greater with H in right mPFC. Finally, compared to AFR, MS reduced and H enhanced hemispheric synchronization of LFP activity with FG-7142 treatment in a dose-dependent manner.These results indicate that functionally-relevant alterations in mPFC GABA transmission are programmed by the early rearing environment in a hemisphere-dependent manner. These findings may model the hemispheric specialization of mPFC function thought to mediate adaptive coping responses to stressors. They also suggest the possibility that early environmental programming of hemispheric functional coupling in mPFC is involved in conferring vulnerability or resilience to stressors later in life.

Electrophysiological insights into the enduring effects of early life stress on the brain

“…Stevenson et al (2008a) demonstrated reduced neuronal firing rates in medial prefrontal cortex in adult hooded rats subjected to 6 h of maternal separation from P2-14. Additionally, these authors observed a differential effect of FG-7142, a benzodiazepine receptor partial inverse agonist thought to mimic stress responses, indicating a likely effect of the maternal separation on GABAergic transmission (Stevenson et al 2008b).…”

“…The relative contributions of these three sources are not yet known, but it seems clear the net result of seizures is CORT release. Given that CORT has been shown to exacerbate seizure-associated phenomena including neural injury (Rosen et al 1994;Sapolsky 1986, Bartesaghi et al 2006Galanopoulou 2008Edwards et al 2002Kinkead et al 2008Blaise et al 2008Hsu et al 2003Lai et al 2006Bronzino et al 1996Stevenson et al 2008a, b Salzberg et al 2007Gruss et al 2008 Kindling rate Kehoe et al 19955-HT Edwards et al 2002Kehoe and Bronzino 1999Arborelius et al 2004Gilby et al 2009Ryan et al 2009 Lambas-Senas et al 2009Jones et al 2009Oomen et al 2010a, b Gartside et al 2003Salzberg et al 2007Stewart et al 2004 Goodfellow a In most studies, early handling has long-term 'stress inoculation' effects on a range of outcomes; in some studies, it has apparently adverse outcomes 1996; Smith-Swintosky et al 1996;Talmi et al 1995), elevated CORT release in maternally separated rats may contribute to the accelerated epileptogenesis seen in those animals. The elevated CORT surge was predicted on the basis of extensive other evidence of early life programming of HPA function by stress (Phillips 2007;Seckl 2008).…”

Maternal separation disrupts dendritic morphology of neurons in prefrontal cortex, hippocampus, and nucleus accumbens in male rat offspring

“…However, layer 3 prelimbic PFC pyramidal neurons and the medium spiny neurons of the NAcc both receive direct excitatory projections from area CA1/subiculum of the hippocampus (Jay and Witter, 1991;Aylward and Totterdell, 1993;Thierry et al, 2000). Interestingly, MS produces a decrease in the neural basal activity of the right prefrontal cortex at the adult age (Stevenson et al, 2008) together with a reduction of the expression of the NMDA receptors (Pickering et al, 2006;Roceri et al, 2002) and immunoreactivity to synaptophysin (Andersen and Teicher, 2004) -a protein associated with the synapse in the hippocampus -which suggests that the loss of excitatory afferents during development may participate in this process, since it is known that dendritic growth and spines density are related to the degree of connectivity and afferent activity (McAllister, 2000). For example, decreasing the afferent activity by in vivo NMDA receptor blockade decreases the dendritic growth and branching in the cerebellar and tectal neurons (Kalb, 1994;Vogel and Prittie, 1995;Rajan et al, 1999).…”

Maternal deprivation induces deficits in temporal memory and cognitive flexibility and exaggerates synaptic plasticity in the rat medial prefrontal cortex

“…Interestingly, LTP in HPC-mPFC pathway is NMDA receptor-dependent (Jay, Burette, & Laroche, 1995), and previous reports suggested that LTP deficits or saturation occur under increased level of basal NMDA receptor activity in certain pathological conditions, which are amenable to reversal by the weak NMDA receptor-blocking drug, memantine (Frankiewicz & Parsons, 1999). In this regard, conversely, a reduced basal neuronal activity in the mPFC of MS rats (Stevenson et al, 2008) may have resulted in the facilitation of LTP induction in these rats. Indeed, it is possible that early MS permanently affects the synaptic plasticity since the first 2-3 postnatal weeks are a critical period for NMDA receptor expression and establishment of synaptic connections (Babb et al, 2005).…”

“…The MS indeed results in various impairments of the PFC in adolescent and adult rats, including modified proteins expression (Brenhouse & Andersen, 2011;Chocyk, Dudys, Przyborowska, Mać kowiak, & Wę dzony, 2010), changed dendritic morphology (Monroy, Hernandez-Torres, & Flores, 2010;Muhammad & Kolb, 2011;Pascual & Zamora-Leon, 2007) and altered neuronal activity (Benekareddy, Goodfellow, Lambe, & Vaidya, 2010;Stevenson, Halliday, Marsden, & Mason, 2008). In human, functional imaging studies reveal structural and functional impairments in the PFC in patients with psychiatric disorders, particularly those reporting childhood maltreatment or adversity (Tomoda et al, 2009;van Harmelen et al, 2010).…”