Access to a high resource environment protects against accelerated maturation following early life stress: A translational animal model of high, medium and low security settings.

Early life exposure to a low security setting, characterized by a scarcity of resources and limited food access, increases the risk for psychiatric illness and metabolic dysfunction. We utilized a translational rat model to mimic a low security environment and determined how this manipulation affected offspring behavior, metabolism, and puberty. Because food insecurity in humans is associated with reduced access to healthy food options the "low security" rat manipulation combined a Western diet with exposure to a limited bedding and nesting manipulation (WD-LB). In this setting, dams were provided with limited nesting materials during the pups' early life (P2-P10). This manipulation was contrasted with standard rodent caging (SD) and environmental enrichment (EE), to model "medium security" and "high security" environments, respectively. To determine if transitioning from a low to high security environment improved outcomes, some juvenile WD-LB offspring were exposed to EE. Maternal care was impacted by these environments such that EE dams engaged in high quality care when on the nest, but spent less time on the nest than SD dams. Although WD-LB dams excessively chased their tails, they were very attentive to their pups, perhaps to compensate for limited resources. Offspring exposed to WD-LB only displayed subtle changes in behavior. However, WD-LB exposure resulted in significant metabolic dysfunction characterized by increased body weight, precocious puberty and alterations in the hypothalamic kisspeptin system. These negative effects of WD-LB on puberty and weight regulation were mitigated by EE exposure. Collectively, these studies suggest that both compensatory maternal care and juvenile enrichment can reduce the impact of a low security environment. Moreover, they highlight how utilizing diverse models of resource (in)stability can reveal mechanisms that confer vulnerability and resilience to early life stress.

Targeted sensory enrichment interventions protect against behavioral and neuroendocrine consequences of early life stress.

Both basic and clinical research support the use of tactile stimulation to rescue several neurobiobehavioral consequences that follow early life stress. Here, using a translational rodent model of the neonatal intensive care unit (NICU), we tested the individual prophylactic potential of a variety of sensory interventions including tactile (brushing pups with a paint brush to mimic maternal licking), auditory (a simulated lactating rat dam heart beat), and olfactory (a series of aroma therapy scents) stimulation. The NICU model was developed to mimic not only the reduced parental contact that sick infants receive (by isolating rat pups from their litters), but also the nosocomial infections and medical manipulations associated with this experience (by utilizing a dual lipopolysaccharide injection schedule). Each of the neurobiobehavioral consequences observed were dissociable between isolation and inflammation, or required a combined presentation ('two hits') of the neonatal stressors. Sprague-Dawley rats exposed to these early life stressors presented with sex-specific disruptions in both separation-induced ultrasonic vocalization (USV) distress calls (males & females) and juvenile social play USVs (males only). All three sensory enhancement interventions were associated with the rescue of potentiated distress calls while olfactory stimulation was protective of social vocalizations. Female rats exposed to early life stress experienced precocious puberty and shifts in the hypothalamic GnRh axis; sensory enrichment counter-acted the advanced pubertal onset. Animals that underwent the NICU protocol also displayed maturational acceleration in terms of the loss of the rooting reflex in addition to hyperalgesia, a reduced preference for a novel conspecific, blunted basal plasma corticosterone and reduced hippocampal glucocorticoid receptor expression. These alterations closely simulated the clinical effects of early life adversity in terms of disruptions in the hypothalamic pituitary "stress" axis, social communication and engagement, tactile system processing, and accelerated maturation. Moreover, sensory enrichment attenuated many of these behavioral and neurophysiological alterations, and even slowed maturation. Overall, this supports the translatability of our novel rodent model and its potential utility in understanding how brain maturation and quality of early life experiences may interact to shape the integrity of stress and sensory system development. Future work must determine the appropriate modalities and parameters (e.g. patterning, timing) for effective sensory enrichment interventions.

Neuroprotective activity of macamides on manganese-induced mitochondrial disruption in U-87 MG glioblastoma cells.

Macamides are a distinct class of secondary metabolites, benzylamides of long chain fatty acids, which were isolated from the Peruvian plant Lepidium meyenii (Maca). As structural analogues of the endocannabinoid anandamide (AEA), they have demonstrated neuroprotective effects in vitro and in vivo. The purpose of this study was to demonstrate the neuroprotective activity of the macamides: N-(3-methoxybenzyl)oleamide (MAC 18:1), N-(3-methoxybenzyl)linoleamide (MAC 18:2) and N-(3-methoxybenzyl)linolenamide (MAC 18:3) in a neurotoxic environment caused by exposure of U-87 MG glioblastoma cells to manganese chloride (MnCl2). The neuroprotective effects of these macamides were reversed by the CB1 antagonist AM251. The mechanism by which manganese (Mn) induces cell damage was investigated by studying its effects on mitochondria. Reactive oxygen species (ROS) increase intracellular calcium and enhance the opening of mitochondrial permeability transition pores (MPTP), which leads to decreased mitochondrial membrane potential (MMP), to disruption of mitochondria and to neuron death in neurodegenerative disorders. In this study, MnCl2 at 50µM was responsible for mitochondrial disruption, which was attenuated by all three of the macamides tested. Human peroxisome proliferator-activated receptor gamma (PPARγ) has been proposed to be a cannabinoid target, and PPARγ has also been demonstrated to mediate some of the longer-term vascular effects of the plant cannabinoid, ∆9-tetrahydrocannabinol. PPARγ activation was observed in response to exposures of cells to MAC 18:2 and MAC 18:3. These findings suggest that macamides achieve their neuroprotective effects by binding to CB1 receptors to protect against Mn-induced toxicity in U-87 MG glioblastoma cells. Additionally these macamides, in a manner similar to the analogous endocannabinoid AEA, interact with other targets such as PPARγ to regulate metabolism and energy homeostasis, cell differentiation and inflammation.