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Preterm infants are at risk for a broad spectrum of neurobehavioral disabilities associated with diffuse disturbances in cortical growth and development. During brain development, subplate neurons (SPNs) are a largely transient population that serves a critical role to establish functional cortical circuits. By dynamically integrating into developing cortical circuits, they assist in consolidation of intracortical and extracortical circuits. Although SPNs reside in close proximity to cerebral white matter, which is particularly vulnerable to oxidative stress, the susceptibility of SPNs remains controversial. We determined SPN responses to two common insults to the preterm brain: hypoxia-ischemia and hypoxia. We used a preterm fetal sheep model using both sexes that reproduces the spectrum of human cerebral injury and abnormal cortical growth. Unlike oligodendrocyte progenitors, SPNs displayed pronounced resistance to early or delayed cell death from hypoxia or hypoxia-ischemia. We thus explored an alternative hypothesis that these insults alter the maturational trajectory of SPNs. We used DiOlistic labeling to visualize the dendrites of SPNs selectively labeled for complexin-3. SPNs displayed reduced basal dendritic arbor complexity that was accompanied by chronic disturbances in SPN excitability and synaptic activity. SPN dysmaturation was significantly associated with the level of fetal hypoxemia and metabolic stress. Hence, despite the resistance of SPNs to insults that trigger white matter injury, transient hypoxemia disrupted SPN arborization and functional maturation during a critical window in cortical development. Strategies directed at limiting the duration or severity of hypoxemia during brain development may mitigate disturbances in cerebral growth and maturation related to SPN dysmaturation. SIGNIFICANCE STATEMENT The human preterm brain commonly sustains blood flow and oxygenation disturbances that impair cerebral cortex growth and cause life-long cognitive and learning disabilities. We investigated the fate of subplate neurons (SPNs), which are a master regulator of brain development that plays critical roles in establishing cortical connections to other brain regions. We used a preterm fetal sheep model that reproduces key features of brain injury in human preterm survivors. We analyzed the responses of fetal SPNs to transient disturbances in fetal oxygenation. We discovered that SPNs are surprisingly resistant to cell death from low oxygen states but acquire chronic structural and functional changes that suggest new strategies to prevent learning problems in children and adults that survive preterm birth., (Copyright © 2017 the authors 0270-6474/17/3711912-18$15.00/0.)

Objective: Recently, we reported that the neocortex displays impaired growth after transient cerebral hypoxia-ischemia (HI) at preterm gestation that is unrelated to neuronal death but is associated with decreased dendritic arbor complexity of cortical projection neurons. We hypothesized that these morphological changes constituted part of a more widespread neuronal dysmaturation response to HI in the caudate nucleus (CN), which contributes to motor and cognitive disability in preterm survivors., Methods: Ex vivo magnetic resonance imaging (MRI), immunohistochemistry, and Golgi staining defined CN growth, cell death, proliferation, and dendritic maturation in preterm fetal sheep 4 weeks after HI. Patch-clamp recording was used to analyze glutamatergic synaptic currents in CN neurons., Results: MRI-defined growth of the CN was reduced after ischemia compared to controls. However, no significant acute or delayed neuronal death was seen in the CN or white matter. Nor was there significant loss of calbindin-positive medium spiny projection neurons (MSNs) or CN interneurons expressing somatostatin, calretinin, parvalbumin, or tyrosine hydroxylase. Morphologically, ischemic MSNs showed a markedly immature dendritic arbor, with fewer dendritic branches, nodes, endings, and spines. The magnitude and kinetics of synaptic currents, and the relative contribution of glutamate receptor subtypes in the CN were significantly altered., Interpretation: The marked MSN dendritic and functional abnormalities after preterm cerebral HI, despite the marked resistance of immature CN neurons to cell death, are consistent with widespread susceptibility of projection neurons to HI-induced dysmaturation. These global disturbances in dendritic maturation and glutamatergic synaptic transmission suggest a new mechanism for long-term motor and behavioral disabilities in preterm survivors via widespread disruption of neuronal connectivity., (© 2014 American Neurological Association.)

The molecular mechanisms that mediate genetic variability in response to alcohol are unclear. We found that alcohol had opposite actions (enhancement or suppression) on GABA(A) receptor (GABA(A)R) inhibition in granule cells from the cerebellum of behaviorally sensitive, low alcohol-consuming Sprague-Dawley rats and DBA/2 mice and behaviorally insensitive, high alcohol-consuming C57BL/6 mice, respectively. The effect of alcohol on granule cell GABA(A)R inhibition was determined by a balance between two opposing effects: enhanced presynaptic vesicular release of GABA via alcohol inhibition of nitric oxide synthase (NOS) and a direct suppression of the activity of postsynaptic GABA(A)Rs. The balance of these two processes was determined by differential expression of neuronal NOS (nNOS) and postsynaptic PKC activity, both of which varied across the rodent genotypes. These findings identify opposing molecular processes that differentially control the magnitude and polarity of GABA(A)R responses to alcohol across rodent genotypes.

In many rodent brain regions, alcohol increases vesicular release of GABA, resulting in an increase in the frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) and the magnitude of tonic GABAA receptor (GABAAR) currents. A neglected issue in translating the rodent literature to humans is the possibility that phylogenetic differences alter the actions of alcohol. To address this issue we made voltage-clamp recordings from granule cells (GCs) in cerebellar slices from the non-human primate (NHP), Macaca fascicularis. We found that similar to Sprague Dawley rats (SDRs), NHP GCs exhibit a tonic conductance generated by α6δ subunit containing GABAARs, as evidenced by its blockade by the broad spectrum GABAAR antagonist, GABAzine (10 μM), inhibition by α6 selective antagonist, furosemide (100 μM), and enhancement by THDOC (10-20 nM) and THIP (500 nM). In contrast to SDR GCs, in most NHP GCs (~60%), application of EtOH (25-105 mM) did not increase sIPSC frequency or the tonic GABAAR current. In a minority of cells (~40%), EtOH did increase sIPSC frequency and the tonic current. The relative lack of response to EtOH was associated with reduced expression of neuronal nitric oxide synthase (nNOS), which we recently reported mediates EtOH-induced enhancement of vesicular GABA release in rats. The EtOH-induced increase in tonic GABAAR current was significantly smaller in NHPs than in SDRs, presumably due to less GABA release, because there were no obvious differences in the density of GABAARs or GABA transporters between SDR and NHP GCs. Thus, EtOH does not directly modulate α6δ subunit GABAARs in NHPs. Instead, EtOH enhanced GABAergic transmission is mediated by enhanced GABA release. Further, SDR GC responses to alcohol are only representative of a subpopulation of NHP GCs. This suggests that the impact of EtOH on NHP cerebellar physiology will be reduced compared to SDRs, and will likely have different computational and behavioral consequences.

This is the first of two papers on the electrosensory lobe (ELL) of mormyrid electric fish. The ELL is the first stage in the central processing of electrosensory information from electroreceptors. Cells of the mormyrid ELL are affected at the time of the electric organ discharge (EOD) by two different inputs, EOD-evoked reafferent input from electroreceptors and corollary discharge input associated with the motor command that elicits the EOD. This first paper examines the intracellular responses of ELL cells to these two different inputs in the region of ELL that receives primary afferent fibers from mormyromast electroreceptors. Mormyromast electroreceptors are responsible for active electrolocation. The paper extends previous studies of the mormyrid ELL by describing the physiological responses of cell types, which had been previously identified only morphologically, including: the two types of Purkinje-like medium ganglionic cells, MG1 and MG2; the thick smooth dendrite cells; and the medium fusiform cells. In addition, two previously unrecognized cell types, the large thick smooth dendrite cell and the interzonal cell, are described both morphologically and physiologically for the first time. Finally, new information is provided on the two types of ELL efferent cells, the large ganglionic and large fusiform cells. All cell types, except for the medium fusiform cell, show nonlinear interactions between electrosensory and corollary discharge inputs. All cell types, except for the medium fusiform cell and the interzonal cell, also show plasticity of the corollary discharge response after pairing with electrosensory stimuli.

This is the second in a series of two papers on the mormyromast regions of the electrosensory lobe (ELL) of mormyrid electric fish. In this study, we examined the effects of artificial stimulation of two of the three major central inputs to ELL on different morphologically identified cell types of ELL. The three major central inputs to ELL are the eminentia granularis posterior, the juxtalobar nucleus, and the preeminential nucleus. We stimulated the juxtalobar and preeminential nuclei. We compared the effects of such stimulation with effects of the electric organ corollary discharge (EOCD) on the same cells to understand the origins of EOCD effects in ELL. Responses to juxtalobar stimulation were different in different cell types and remarkably similar to corollary discharge responses in the same cells. In addition, responses to juxtalobar stimulation were consistently depressed when the stimulus was delivered immediately after the naturally occurring EOCD response. These findings indicate that the juxtalobar nucleus is a major source of the EOCD responses of ELL cells. In contrast, preeminential stimulation evoked similar responses in medium ganglionic cells, and the two types of efferent cells that were quite different from the EOCD responses of these cells, suggesting that the preeminential nucleus is less important than the juxtalobar nucleus in determining the EOCD responses of ELL cells. Preeminential responses of medium ganglionic and efferent cells consisted of a short-latency excitatory postsynaptic potential (EPSP) followed by a long-lasting inhibitory postsynaptic potential (IPSP). Both the EPSPs and IPSPs were facilitated when brief bursts of closely spaced stimuli were delivered.

The neurobiological mechanisms that regulate the appetite-stimulatory properties of cannabis sativa are unresolved. This work examined the hypothesis that cannabinoid-1 receptor (CB1R) expressing neurons in the mediobasal hypothalamus (MBH) regulate increased appetite following cannabis vapor inhalation. Here we utilized a paradigm where vaporized cannabis plant matter was administered passively to rodents. Initial studies in rats characterized meal patterns and operant responding for palatable food following exposure to air or vapor cannabis. Studies conducted in mice used a combination of in vivo optical imaging, electrophysiology and chemogenetic manipulations to determine the importance of MBH neurons for cannabis-induced feeding behavior. Our data indicate that cannabis vapor increased meal frequency and food seeking behavior without altering locomotor activity. Importantly, we observed augmented MBH activity within distinct neuronal populations when mice anticipated or consumed food. Mechanistic experiments demonstrated that pharmacological activation of CB1R attenuated inhibitory synaptic tone onto hunger promoting Agouti Related Peptide (AgRP) neurons within the MBH. Lastly, chemogenetic inhibition of AgRP neurons attenuated the appetite promoting effects of cannabis vapor. Based on these results, we conclude that MBH neurons contribute to the appetite stimulatory properties of inhaled cannabis. [ABSTRACT FROM AUTHOR]

The endocannabinoid system plays important roles in brain development, but mechanistic studies have focused on neuronal differentiation, migration, and synaptogenesis, with less attention to transcellular interactions that coordinate neurodevelopmental processes across developing neural networks. We determined that, in the developing rodent cerebellar cortex (of both sexes), there is a transient window when the dominant brain cannabinoid receptor, CB1R, is expressed on afferent terminals instead of output neuron Purkinje cell synapses that dominate the adult cerebellum. Activation of these afferent CBIRs suppresses synaptic transmission onto developing granule cells, and consequently also suppresses excitation of downstream neurons in the developing cortical network, including nonsynaptic, migrating neurons. Application of a CB1R antagonist during afferent stimulation trains and depolarizing voltage steps caused a significant, sustained potentiation of synaptic amplitude. Our data demonstrate that transiently expressed afferent CBIRs regulate afferent synaptic strength during synaptogenesis, which enables coordinated dampening of transcortical developmental signals. [ABSTRACT FROM AUTHOR]

Brain ischemia results from cardiac arrest, stroke or head trauma. These conditions can cause severe brain damage and are a leading cause of death and long-term disability. Neurons are far more susceptible to ischemic damage than neighboring astrocytes, but astrocytes have diverse and important functions in many aspects of ischemic brain damage. Here we review three main roles of astrocytes in ischemic brain damage. First, we consider astrocyte glycogen stores, which can defend the brain against hypoglycemic brain damage but may aggravate brain damage during ischemia due to enhanced lactic acidosis. Second, we review recent breakthroughs in understanding astrocytic mechanisms of transmitter release, particularly for those transmitters with known roles in ischemic brain damage: glutamate, D-serine, ATP and adenosine. Third, we discuss the role of gap-junctionally connected networks of astrocytes in mediating the spread of damaging molecules to healthy 'bystanders' during infarct expansion in stroke. [ABSTRACT FROM AUTHOR]