Biology subjects

Borgland, S. L.

Publications and source records attributed to Borgland, S. L..

4 recordsLinked to original sources

bioRxiv2020

Sex differences in the effect of acute fasting on excitatory and inhibitory synapses onto ventral tegmental area dopamine neurons

Dopamine neurons in the ventral tegmental area (VTA) are important for energizing goal directed behaviour towards food and are sensitive to changes in metabolic states. Fasting increases the incentive motivation for food, mobilization of energy stores and have sex-dependent effects. However, it is unknown how acute fasting alters excitatory or inhibitory synaptic transmission onto VTA dopamine neurons. An acute 16h overnight fast induced increased food seeking behaviour that was more predominant in male mice. Fasting increased miniature excitatory postsynaptic current (mEPSC) frequency and amplitude in male, but not female mice. This effect was not due to altered release probability as there was no change in the paired pulse ratio, nor was it due to an altered postsynaptic response as there was no change in the AMPAR/NMDA ratio or response to glutamate uncaging. However, this effect was consistent with an increase in the number of release sites. In addition, depolarization-induced-suppression of excitation (DSE), a measure of short-term endocannabinoid-mediated plasticity, was enhanced in female but not male fasted mice. There were no fasting-induced changes at inhibitory synapses onto dopamine neurons of male or female mice. Taken together, these results demonstrate that fasting influences excitatory synapses differentially in male and female mice, but preserves inhibitory synapses onto dopamine neurons, indicating that the mesolimbic circuit of male and female mice respond differently to acute energy deprivation. Key PointsO_LIFasting can increase motivation for food and can energize reward-seeking. C_LIO_LIVentral tegmental area (VTA) dopamine neurons respond to motivationally relevant information and fasting can influence mesolimbic dopamine concentration. C_LIO_LIAn acute overnight fast differentially alters food approach behaviours and excitatory synaptic transmission onto VTA dopamine neurons of male or female mice. C_LIO_LIWhile inhibitory synapses onto VTA dopamine neurons are not altered by fasting in male or female mice, male mice had strengthened excitatory synapses whereas female mice had increased endocannabinoid-mediated short term plasticity at excitatory synapses. C_LIO_LIThese results help us understand how fasting differentially influences excitatory synaptic transmission onto dopamine neurons and may inform different strategies for fasting-induced food seeking by male and female mice. C_LI

neuroscience↗

bioRxiv2020

Mu-opioids suppress GABAergic synaptic transmission onto orbitofrontal cortex pyramidal neurons with regional selectivity.

The orbitofrontal cortex (OFC) plays a critical role in evaluating outcomes in a changing environment. Administering opioids to the OFC can alter the hedonic reaction to food rewards and increase their consumption in a subregion specific manner. However, it is unknown how mu-opioid signalling influences synaptic transmission in the OFC. Thus, we investigated the cellular actions of mu-opioids within distinct subregions of the OFC. Using in-vitro patch clamp electrophysiology in brain slices containing the OFC, we found that the mu-opioid agonist, DAMGO produced a concentration-dependant inhibition of GABAergic synaptic transmission onto medial OFC (mOFC), but not lateral OFC (lOFC) neurons. This effect was mediated by presynaptic mu-opioid receptor activation of local parvalbumin (PV+)-expressing interneurons. The DAMGO-induced suppression of inhibition was long-lasting and not reversed upon washout of DAMGO, or by application of the mu-opioid receptor antagonist, CTAP, suggesting an inhibitory long-term depression (iLTD) induced by an exogenous mu-opioid. We show that LTD at inhibitory synapses is dependent on downstream cAMP/PKA signaling, which differs between the mOFC and lOFC. Finally, we demonstrate that endogenous opioid release triggered via moderate physiological stimulation can induce LTD. Taken together, these results suggest that presynaptic mu-opioid stimulation of local PV+ interneurons induces a long-lasting suppression of GABAergic synaptic transmission, which depends on subregional differences in mu-opioid receptor coupling to the downstream cAMP/PKA intracellular cascade. These findings provide mechanistic insight into the opposing functional effects produced by mu-opioids within the OFC. Significance StatementConsidering that both the OFC and the opioid system regulate reward, motivation, and food intake; understanding the role of opioid signaling within the OFC is fundamental for a mechanistic understanding of the sequelae for several psychiatric disorders. This study makes several novel observations. First, mu-opioids induce a long-lasting suppression of inhibitory synaptic transmission onto OFC pyramidal neurons in a regionally selective manner. Secondly, mu-opioids recruit PV+ inputs to suppress inhibitory synaptic transmission in the mOFC. Thirdly, the regional selectivity of mu-opioid action of endogenous opioids is due to the efficacy of mu-opioid receptor coupling to the downstream cAMP/PKA intracellular cascades. These experiments are the first to reveal a cellular mechanism of opioid action within the OFC.

neuroscience↗

bioRxiv2020

Obesity-induced astrocyte dysregulation of heterosynaptic plasticity within the orbitofrontal cortex

SO_SCPLOWUMMARYC_SCPLOWOverconsumption of highly palatable, energy dense food is considered a key driver of the obesity pandemic. The orbitofrontal cortex (OFC) is critical for reward valuation of gustatory signals, yet how the OFC adapts to obesogenic diets is poorly understood. Here we show that extended access to a cafeteria diet impairs astrocyte glutamate clearance, which leads to a heterosynaptic depression of GABA transmission onto pyramidal neurons of the OFC. This decrease in GABA tone is due to an increase in extrasynaptic glutamate, which acts via metabotropic glutamate receptors to liberate endocannabinoids. This impaired the induction of endocannabinoid-mediated long-term plasticity. In obese rats, this cascade of synaptic impairments was rescued by restoring astrocyte glutamate transport with the nutritional supplement, N-acetylcysteine. Together, our findings indicate that obesity targets astrocytes to disrupt the delicate balance between excitatory and inhibitory transmission in the OFC. HO_SCPLOWIGHLIGHTSC_SCPLOWO_LIDiet-induced obesity induces hypertrophy of astrocytes and impairs their ability to transport glutamate. C_LIO_LIFailure of astrocytes to clear extrasynaptic glutamate drives endocannabinoid-mediated inhibitory long-term depression of principal output neurons in the OFC. C_LIO_LIAstrocytic glutamate transporter function is restored with NAC, which rescues the synaptic deficits. C_LI

neuroscience↗

bioRxiv2020

Disinhibition of the orbitofrontal cortex biases goal-directed behaviour in obesity

The lateral orbitofrontal cortex (lOFC) receives sensory information about food and integrates these signals with expected outcomes to guide future actions, and thus may play a key role in a distributed network of neural circuits that regulate feeding behaviour. Here, we reveal a novel role for the lOFC in the cognitive control of behaviour in obesity. Food-seeking behaviour is biased in obesity such that in male obese mice, behaviours are less flexible to changes in the perceived value of the outcome. Obesity is associated with reduced lOFC inhibitory drive, and chemogenetic reduction in GABAergic neurotransmission in the lOFC induces obesity-like impairments in goal-directed behaviour. Conversely, pharmacological or optogenetic restoration of inhibitory neurotransmission in the lOFC of obese mice reinstates flexible behaviour. Our results indicate that obesity-induced disinhibition of the lOFC leads to a failure to update changes in the value of food with satiety, which in turn may influence how individuals make decisions in an obesogenic environment.

neuroscience↗