Early life stress impairs postnatal oligodendrogenesis and adult emotional behaviour through activity-dependent mechanisms

Abstract

max 250 words)Exposure to stress during early life (infancy/childhood) has long-term effects on the structure and function of the prefrontal cortex (PFC) and increases the risk for adult depression and anxiety disorders. However, little is known about the molecular and cellular mechanisms of these effects.Here we focused on changes induced by chronic maternal separation during the first two weeks of postnatal life. Unbiased mRNA expression profiling in the medial PFC (mPFC) of maternally separated (MS) pups identified an increased expression of myelin-related genes and a decreased expression of immediate early genes. Oligodendrocyte lineage markers and birthdating experiments indicated a precocious oligodendrocyte differentiation in the mPFC at P15, leading to a depletion of the oligodendrocyte progenitor pool in MS adults. We tested the role of neuronal activity in oligodendrogenesis, using designed receptors exclusively activated by designed drugs (DREADDs) techniques. hM4Di or hM3Dq constructs were transfected into mPFC neurons using fast-acting AAV8 viruses. Reduction of mPFC neuron excitability during the first two postnatal weeks caused a premature differentiation of oligodendrocytes similar to the MS pups, while chemogenetic activation normalized it in the MS animals. Bidirectional manipulation of neuron excitability in the mPFC during the P2-P14 period had long lasting effects on adult emotional behaviours and on temporal object recognition: hM4Di mimicked MS effects, while hM3Dq prevented the pro-depressive effects and short term memory impairment of MS. Thus, our results identify neuronal activity as a critical target of early life stress and demonstrate its function in controlling both postnatal oligodendrogenesis and adult mPFC-related behaviors.

Chronic postnatal chemogenetic activation of forebrain excitatory neurons evokes persistent changes in mood behavior

“…Given that thus far very few studies have used chemogenetic strategies during developmental time windows ( Teissier et al, 2020 ; Wong et al, 2018 ), we characterized the consequences of hM3Dq DREADD activation of forebrain excitatory neurons in the postnatal window using both electrophysiological and biochemical approaches. Our observation of hM3Dq DREADD-mediated induction of robust spiking activity in postnatal slices parallels observations made in adulthood ( Alexander et al, 2009 ; Pati et al, 2019 ).…”

“…We also addressed the possibility that off-target effects of CNO ( Gomez et al, 2017 ; MacLaren et al, 2016 ) may impact our interpretations by extensively addressing effects of postnatal CNO treatment to genotype-control or background strain mouse pups, and noted no change in the emergence of anxiety- or despair-like behaviors in adulthood. These controls are particularly relevant given that very few reports have used chemogenetic perturbations during these early postnatal windows ( Teissier et al, 2020 ; Wong et al, 2018 ). Our results do not allow us to completely rule out potential off-target effects of PNCNO treatment on locomotion in the OFT in adulthood.…”

“…Activity within cortical pyramidal neurons can directly shape interneuron survival ( Wong et al, 2018 ), thus influencing the manner in which the optimal balance between excitatory and inhibitory neurons in cortical microcircuits is established. A recent report indicates that hM3Dq DREADD activation of the medial prefrontal cortex during postnatal life can abrogate the influence of maternal separation on oligodendrogenesis and despair-like behavior ( Teissier et al, 2020 ). However, the use of a pan-neuronal human synapsin promoter to drive the hM3Dq DREADD ( Teissier et al, 2020 ), and the absence of a non-maternal separation cohort makes it difficult to directly compare with our results.…”

“…A recent report indicates that hM3Dq DREADD activation of the medial prefrontal cortex during postnatal life can abrogate the influence of maternal separation on oligodendrogenesis and despair-like behavior ( Teissier et al, 2020 ). However, the use of a pan-neuronal human synapsin promoter to drive the hM3Dq DREADD ( Teissier et al, 2020 ), and the absence of a non-maternal separation cohort makes it difficult to directly compare with our results. Our observations support the view that chemogenetic activation of forebrain excitatory neurons from P2 to 14 could impinge on several key neurodevelopmental processes, thus establishing a substrate for the emergence of perturbed mood-related behaviors in adulthood.…”

Early life stress programming of NG2+ glia transcriptome alters functional properties of voltage gated sodium (Nav) channels and cognitive performance

“…Myelinating cells -oligodendrocytes within the central nervous system-derive from the differentiation of oligodendrocyte precursor cells (OPCs) (15). Both OPCs and mature oligodendrocytes can be affected by early stressful experiences (16,17). The OPCs expressing the type I proteoglycan CSPG4 (NG2) on their cell surface -known as NG2+ cells -has been discussed to also fulfill physiological roles in brain homeostasis, although the mechanistic nature of such roles remains unclear.…”