How Do Cells of the Oligodendrocyte Lineage Affect Neuronal Circuits to Influence Motor Function, Memory and Mood?

Oligodendrocyte progenitor cells (OPCs) are immature cells in the central nervous system (CNS) that can rapidly respond to changes within their environment by modulating their proliferation, motility and differentiation. OPCs differentiate into myelinating oligodendrocytes throughout life, and both cell types have been implicated in maintaining and modulating neuronal function to affect motor performance, cognition and emotional state. However, questions remain about the mechanisms employed by OPCs and oligodendrocytes to regulate circuit function, including whether OPCs can only influence circuits through their generation of new oligodendrocytes, or can play other regulatory roles within the CNS. In this review, we detail the molecular and cellular mechanisms that allow OPCs, newborn oligodendrocytes and pre-existing oligodendrocytes to regulate circuit function and ultimately influence behavioral outcomes

Mesolimbic dopamine and its neuromodulators in obesity and binge eating

Obesity has reached epidemic prevalence, and much research has focused on homeostatic and nonhomeostatic mechanisms underlying overconsumption of food. Mesocorticolimbic circuitry, including dopamine neurons of the ventral tegmental area (VTA), is a key substrate for nonhomeostatic feeding. The goal of the present review is to compare changes in mesolimbic dopamine function in human obesity with diet-induced obesity in rodents. Additionally, we will review the literature to determine if dopamine signaling is altered with binge eating disorder in humans or binge eating modeled in rodents. Finally, we assess modulation of dopamine neurons by neuropeptides and peripheral peptidergic signals that occur with obesity or binge eating. We find that while decreased dopamine concentration is observed with obesity, there is inconsistency outside the human literature on the relationship between striatal D2 receptor expression and obesity. Finally, few studies have explored how orexigenic or anorexigenic peptides modulate dopamine neuronal activity or striatal dopamine in obese models. However, ghrelin modulation of dopamine neurons may be an important factor for driving binge feeding in rodents

GABA(B) modulation of dopamine release in the nucleus accumbens core

Modulation of the concentration of dopamine (DA) released from dopaminergic terminals in the nucleus accumbens (NAc) influences behaviours such as the motivation to obtain drugs of abuse. γ-Aminobutyric acid type B (GABAB ) receptors are expressed throughout the mesolimbic circuit, including in the NAc, and baclofen, an agonist of GABAB receptors, can decrease drug-seeking behaviours. However, the mechanism by which GABAB receptors modulate terminal DA release has not been well studied. We explored how baclofen modulates the concentration of DA released from terminals in the NAc core using fast-scan cyclic voltammetry in brain slices from adult male C57BL/6J mice. We found that baclofen concentration-dependently decreased single pulse-evoked DA release. This effect was blocked by the GABAB antagonist, CGP 52432, but not by a nicotinic acetylcholine receptor antagonist. Suppression of DA release by a saturating concentration of baclofen was sustained for up to 1 h. The effect of baclofen was reduced with electrical stimulations mimicking burst firing of DA neurons. Similar to the D2 receptor agonist, quinpirole, baclofen reduced the probability of DA release, supporting a mechanistic overlap with D2 receptors. Baclofen-mediated suppression of DA release persisted after a locomotor-sensitizing cocaine treatment, indicating that GABAB receptors on DA terminals were not altered by cocaine exposure. These data suggest that baclofen-mediated suppression of terminal DA release is due to GABAB activation on DA terminals to reduce the probability of DA release. This effect does not readily desensitize, and persists regardless of chronic cocaine treatment

Isovaline does not activate GABA(B) receptor-coupled potassium currents in GABA(B) expressing AtT-20 cells and cultured rat hippocampal neurons.

Isovaline is a non-proteinogenic amino acid that has analgesic properties. R-isovaline is a proposed agonist of the γ-aminobutyric acid type B (GABA(B)) receptor in the thalamus and peripheral tissue. Interestingly, the responses to R-isovaline differ from those of the canonical GABA(B) receptor agonist R-baclofen, warranting further investigation. Using whole cell recording techniques we explored isovaline actions on GABA(B) receptors coupled to rectifying K+ channels in cells of recombinant and native receptor preparations. In AtT-20 cells transfected with GABA(B) receptor subunits, bath application of the GABA(B) receptor agonists, GABA (1 μM) and R-baclofen (5 μM) produced inwardly rectifying currents that reversed approximately at the calculated reversal potential for K+ R- isovaline (50 μM to 1 mM) and S-isovaline (500 μM) did not evoke a current. R-isovaline applied either extracellularly (250 μM) or intracellularly (10 μM) did not alter responses to GABA at 1 μM. Co-administration of R-isovaline (250 μM) with a low concentration (10 nM) of GABA did not result in a response. In cultured rat hippocampal neurons that natively express GABA(B) receptors, R-baclofen (5 μM) induced GABA(B) receptor-dependent inward currents. Under the same conditions R-isovaline (1 or 50 μM) did not evoke a current or significantly alter R-baclofen-induced effects. Therefore, R-isovaline does not interact with recombinant or native GABA(B) receptors to open K+ channels in these preparations

GABA and R-baclofen, but not isovaline, evoke inwardly rectifying currents in transfected AtT-20 cells.

<p><b>a)</b> Baseline subtracted IV curve for GABA and GABA + CGP 52432 (n = 7). Inset shows example currents at baseline (black), in the presence of GABA (dark grey) or in the presence of GABA + CGP 52432 (light grey). <b>b</b>) Baseline subtracted IV curve for R-baclofen (n = 6). Inset shows example currents at baseline (black) or in the presence of R-baclofen (dark grey). <b>c</b>) Baseline subtracted IV curves for R-isovaline at three concentration (50 μM n = 6; 250 μM n = 8; 1 mM n = 4). <b>d</b>) Example currents at baseline (black) and on application of three concentrations of R-isovaline (dark grey). <b>e</b>) Baseline subtracted IV curve for S-isovaline (n = 4). Inset shows example currents at baseline (black) or in the presence of S-isovaline (dark grey). <b>f</b>) Summary graph showing the currents recorded at -112.5 mV at baseline (open bars) or on application of GABA, R-baclofen, R-isovaline or S-isovaline (shaded bars). Data are represented as mean ± SEM. *** = p < 0.001.</p

R-isovaline does not modulate GABA-evoked currents in transfected AtT20 cells.

<p><b>a</b>) Baseline subtracted IV curves for GABA (1 μM; n = 3) and co-application of R-isovaline with GABA (1 μM n = 3; 10 nM n = 6). <b>b</b>) Graph shows that R-isovaline does not alter the current evoked by a high concentration of GABA. Inset shows example currents at baseline (black), on application of GABA (1 μM; dark grey) and on co-application of 1 μM GABA with 250 μM R-isovaline (light grey). <b>c</b>) Graph shows that R-isovaline does not alter the current when co-applied with a low concentration of GABA. Inset shows example currents at baseline (black), on application of 1 μM GABA (dark grey), and on co-application of 10 nM GABA with 250 μM R-isovaline (light grey). Data are expressed as mean ± SEM. * = p < 0.05, ** = p < 0.01.</p

R-isovaline does not activate GABA_B receptors in cultured hippocampal neurons.

<p><b>a</b>) Current at a holding potential of -80 mV in a high extracellular K⁺ solution at baseline (open bars) and on application of R-baclofen (n = 7), R-baclofen + CGP 52432 (n = 7) and R-isovaline at low (1 μM; n = 3) and high (50 μM; n = 8) concentrations (shaded bars). <b>b</b>) Example shows R-baclofen-mediated current <b>c</b>) Example shows lack of effect of low concentration of R-isovaline in a cell that responded to R-baclofen both before and after R-isovaline application. <b>d</b>) Example shows the effect of R-baclofen after 5 min pretreatment with 50 μM R-isovaline. <b>e</b>) Example shows the effects of two applications of R-baclofen after prolonged incubation (> 1 hour) with R-isovaline. <b>f</b>) Graph shows the magnitude of the current evoked by 5 μM R-baclofen in control extracellular solution (n = 8), after 5 minutes pretreatment with R-isovaline (n = 4) or after > 1 hour pretreatment with R-isovaline (n = 8). Data represent mean ± SEM. ** = P < 0.01.</p

GABA, R-baclofen and R-isovaline do not evoke currents in untransfected AtT-20 cells.

<p><b>a)</b> Baseline subtracted IV curve for GABA (n = 4), R-baclofen (n = 4) and R-isovaline (n = 5). <b>b</b>) Example currents at the maximum hyperpolarising step (-112.5 mV, voltage step depicted above currents) at baseline (black) and on application (grey) of GABA, R-baclofen or R-isovaline. <b>c</b>) Summary graph showing currents recorded at -112.5 mV at baseline (open bars) and on application of GABA, R-baclofen, or R-isovaline (shaded bars). Data are represented as mean ± SEM.</p

The GABA_B1 subunit expresses at the membrane in transfected AtT-20 cells.

<p>AtT-20 cells were transfected with both subunits for the GABA_B receptor along with GFP (shown in green). Immunohistochemistry was performed for the GABA_B1 subunit (red) and cell nuclei were stained with DAPI (blue). <b>a)</b> Magnified image of an isolated cell demonstrating GABA_B1 subunit protein at the cell membrane in a GFP positive cell. <b>b)</b> Negative control (no primary antibody for GABA_B1). A merged image is shown at the bottom of each column. Scale bars are 5 μm.</p