Traumatic brain injury (TBI) is a major cause of acquired cognitive disability in childhood. Such disability may be blunted by enhancing the brain's endogenous neuroprotective response. An important endogenous neuroprotective response is the insulin-like growth factor-1 (IGF-1) mRNA variant, IGF-1B. IGF-1B mRNA, characterized by exon 5 inclusion, encodes the IGF-1 and Eb peptides. IGF-1A mRNA excludes exon 5 and encodes the IGF-1 and Ea peptides. A region in the human IGF-1B homologue acts as an exon-splicing enhancer (ESE) to increase IGF-1B mRNA. It is not known if TBI is associated with increased brain IGF-1B mRNA. Epigenetic modifications may underlie altered gene expression in the brain after TBI. We hypothesized that TBI would increase hippocampal IGF-1B mRNA in 17-day-old rats, associated with DNA methylation and/or histone modifications at the promoter site 1 (P1) or exon 5/ESE region. Hippocampi from rat pups after controlled cortical impact (CCI) were used to measure IGF-1B mRNA, DNA methylation, and histone modifications at the P1, P2, and exon5/ESE regions. In CCI hippocampi, IGF-1B mRNA peaked at post-injury day (PID) 2 (1700±320% sham), but normalized by PID 14. IGF-1A peaked at PID 3 (280±52% sham), and remained elevated at PID 14. Increased IGF-1B mRNA was associated with increased methylation at P1, and increased histone modifications associated with gene activation at P2 and exon5/ESE, together with differential methylation in the exon 5/ESE regions. We report for the first time that hippocampal IGF-1B mRNA increased after developmental TBI. We speculate that epigenetic modifications at the P2 and exon 5/ESE regions are important in the regulation of IGF-1B mRNA expression. The exon 5/ESE region may present a means for future therapies to target IGF-1B transcription after TBI.

The action of glucocorticoids (GC) on neuronal cell membrane was studied in isolated and superfused guinea pig coeliac ganglia by the intracellular recording technique. Cortisol succinate (F) hyperpolarized the membrane potential of 47 of 179 cells and changed the cell’s input resistance with a latency of less than 2 min in vitro. The effect persisted under low Ca²⁺/high Mg²⁺ superfusing condition and could be blocked by RU 38486, a competitive antagonist of GC cytosolic receptor. Cortisol-21-bovine albumin conjugant exhibited the same effect. Corticosterone (B) elicited hyperpolarization in another 15 of 83 cells, but dexamethasone (Dex) did not. Dex, however, depolarized 2 of 18 cells. Aldosterone, cholesterol and vehicle (ethyl alcohol) caused no detectable change in membrane potential. In vivo studies by iontophoretic application of steroids to hypothalamic paraventricular (PVN) neurons showed that F inhibited the unit discharges in 68 of 97 PVN neurons, and the effect could be antagonized by RU 38486. Dex excited 30 of 100 neurons. Estradiol (E) also inhibited the discharges, but this inhibition was not antagonized by RU 38486. The effect of GC on PVN neurons was also examined in hypothalamic slices including the paraventricular nucleus. B inhibited 28 of 104 units and excited 7 of 104 cells, and both effects could be antagonized by RU 38486. The threshold of inhibitory response was about 10^–7M, which is close to the physiological level of the hormone in plasma. The results suggest that GC can act non-genomically and specifically through its membrane receptor on the neuronal surface, and that there might be a chemical similarity between the membrane receptor and the traditional cytosolic GC receptor. It is also suggested that the modulatory action of GV might have some important physiological significance.

Intrauterine growth restriction (IUGR) programs neurodevelopmental impairment and long-term neurological morbidities. Neurological morbidities in IUGR infants are correlated with changes hippocampal volume. We previously demonstrated that IUGR alters hippocampal cellular composition in both neonatal and juvenile rat pups in association with altered hippocampal gene expression and epigenetic determinants. PPARγ signaling is important for neurodevelopment as well as epigenetic integrity in the brain via the PPARγ-Setd8-H4K20me1 axis and Wnt signaling. We hypothesized that IUGR would decrease expression of PPARγ, Setd8, and H4K20me1 in juvenile rat hippocampus. We further hypothesized that reduced PPARγ-Setd8-H4K20me1 would be associated with reduced Wnt signaling genes Wnt3a and β-catenin, and wnt target gene Axin2. To test our hypothesis we used a rat model of uteroplacental insufficiency-induced IUGR. We demonstrated that PPARγ localizes to oligodendrocytes, neurons and astrocytes within the juvenile rat hippocampus. We also demonstrated that IUGR reduces levels of PPARγ, Setd8 and H4K20me1 in male and female juvenile rat hippocampus in conjunction with reduced Wnt signaling components in only male rats. We speculate that reduced PPARγ and Wnt signaling may contribute to altered hippocampal cellular composition which, in turn, may contribute to impaired neurodevelopment and subsequent neurocognitive impairment in IUGR offspring.

The prefrontal cortex has been implicated in various cognitive processes, including working memory, executive control, decision making, and relational learning. One core computational requirement underlying all these processes is the integration of information across time. When rodents and rabbits associate two temporally discontiguous stimuli, some neurons in the medial prefrontal cortex (mPFC) change firing rates in response to the preceding stimulus and sustain the firing rate during the subsequent temporal interval. These firing patterns are thought to serve as a mechanism to buffer the previously presented stimuli and signal the upcoming stimuli; however, how these critical properties are distributed across different neuron types remains unknown. We investigated the firing selectivity of regular-firing, burst-firing, and fast-spiking neurons in the prelimbic region of the mPFC while rats associated two neutral conditioned stimuli (CS) with one aversive stimulus (US). Analyses of firing patterns of individual neurons and neuron ensembles revealed that regular-firing neurons maintained rich information about CS identity and CS-US contingency during intervals separating the CS and US. Moreover, they further strengthened the latter selectivity with repeated conditioning sessions over a month. The selectivity of burst-firing neurons for both stimulus features was weaker than that of regular-firing neurons, indicating the difference in task engagement between two subpopulations of putative excitatory neurons. In contrast, putative inhibitory, fast-spiking neurons showed a stronger selectivity for CS identity than for CS-US contingency, suggesting their potential role in sensory discrimination. These results reveal a fine-scaled functional organization in the prefrontal network supporting the formation of temporal stimulus associations. NEW & NOTEWORTHY To associate stimuli that occurred separately in time, the brain needs to bridge the temporal gap by maintaining what was presented and predicting what would follow. We show that in rat medial prefrontal cortex, the former function is associated with a subpopulation of putative inhibitory neurons, whereas the latter is supported by a subpopulation of putative excitatory neurons. Our results reveal a distinct contribution of these microcircuit components to neural representations of temporal stimulus associations.

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