Biology subjects

Borgland, S. L.

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

12 recordsLinked to original sources

bioRxiv2026

Divergent roles of orexin and dynorphin in modulating VTA dopamine projections to the BLA after morphine exposure

Background: Opioid use disorder is associated with persistent alterations in mesolimbic dopamine (DA) circuits, but the circuit- and neuromodulatory mechanisms driving this plasticity remain unclear. Lateral hypothalamic orexin/dynorphin (LHox/dyn) neurons provide dense input to the ventral tegmental area (VTA), where orexin and dynorphin exert opposing actions via orexin 1 receptor (Ox1R) and kappa-opioid (KOR) receptors, respectively. Here, we investigated how opioid dependence alters the selective contributions of optically driven LHox/dyn release on the firing of VTA DA neurons that project to the basolateral amygdala (BLA) or the lateral nucleus accumbens shell (lAcbSh). Methods: We measured the effects optogenetic activation of the LHox/dyn input on VTA DA neuronal activity with retrogradely labeled projection targets after repeated morphine or saline injections or fentanyl self-administration. We used fiber photometry to measure how the LHox/dyn input to the VTA influences dopamine in the BLA in opioid-dependent mice. Results: We found that in saline-treated mice, LHox/dyn predominantly inhibited BLA-projecting VTA DA neurons via KOR signaling. Remarkably, opioids, morphine or fentanyl, shifted the neuromodulatory capacity of LHox/dyn input to BLA-projecting VTA DA neurons from inhibitory to excitatory. This was due to increased dynorphin release in the VTA, leading to reduced function of KORs on BLA-projecting VTA DA neurons. This led to increased BLA DA, which typically encodes the emotional and associative salience of reward-related cues in opioid dependent mice. Conclusions: Together, we define a mechanism of how LHox/dyn corelease independently neuromodulates VTA projections, and how removal of a KOR brake leads to enhanced neuromodulatory activity of dopamine projections to the BLA.

neuroscience↗

bioRxiv2025

Brain serotonin circuit reverses decline in physical activity with age

Physical inactivity increases with age and is the fourth leading risk factor for mortality. Establishing the mechanisms underpinning declining physical activity (PA) with age has remained both elusive and difficult to overcome. Older (50-70 years old) compared with younger (17-30 years old) UK participants showed reduced PA, and this profile was effectively modelled in mice. Analysis of brain serotonin (5-HT) neurons in the dorsal raphe (DR) revealed altered firing activity in older mice. Chemogenetically mimicking this 5-HTDR tone in young adult mice produced an older adult PA profile. Genetically blocking 5-HT activity at 5-HT2C receptors (5-HT2CRs) prevented the decline in PA with age. Importantly, barring 5-HT action at 5-HT2CRs specifically within the ventral tegmental area restored youthful PA levels and strength in older mice. These data fill a longstanding knowledge gap by defining brain circuitry programming the decline in PA with age, and importantly, a means to reverse it.

neuroscience↗

bioRxiv2024

Distinct neuromodulatory effects of endogenous orexin and dynorphin corelease on projection-defined ventral tegmental dopamine neurons.

AbstractDopamine (DA) neurons in the ventral tegmental area (VTA) respond to motivationally relevant cues and circuit-specific signaling drives different aspects of motivated behavior. Orexins (ox; also known as hypocretin) and dynorphin (dyn) are co-expressed lateral hypothalamic (LH) neuropeptides that project to the VTA. These peptides have opposing effects on the firing activity of VTADA neurons via orexin 1 (Ox1R) or kappa opioid (KOR) receptors, respectively. Given that Ox1R activation increases VTADA firing, and KOR decreases firing, it is unclear how the co-released peptides contribute to the net activity of DA neurons. We tested if optical stimulation of LH neuromodulates VTADA neuronal activity via peptide release and if the effects of optically driven LHox/dyn release segregates based on VTADA projection targets including the basolateral amygdala (BLA) or the lateral or medial shell of the nucleus accumbens (lAcbSh, mAchSh). Using a combination of circuit tracing, optogenetics, and patch clamp electrophysiology in male and female orexincre mice we showed a diverse response of LH optical stimulation on VTADA neuronal firing, that are not mediated by fast transmitter release and are blocked by antagonists to KOR and Ox1R signaling. Additionally, where optical stimulation of LHox/dyn inputs in the VTA inhibited firing of the majority of BLA projecting VTADA neurons, optical stimulation of LH inputs in the VTA bidirectionally affects firing of either lAcbSh or mAchSh projecting VTADA neurons. These findings indicate that LHox/dyn corelease may influence the output of the VTA by balancing ensembles of neurons within each population which contribute to different aspects of reward seeking. Significance StatementThe mesolimbic dopamine (DA) system is known to play a crucial role in motivation and reward-learning and receives neuromodulatory input from the lateral hypothalamus (LH). We show that optical stimulation of the orexin-containing LH input in the VTA releases both orexin and dynorphin to bidirectionally alter VTADA firing. Furthermore, orexin and dynorphin differentially modulate firing of DA inputs to the basolateral amygdala, whereby dynorphin predominates, or to the nucleus accumbens which is sensitive to both neuromodulators. Our findings contribute to a more comprehensive understanding of the neuromodulatory effects of coreleased LH orexin and dynorphin on the VTADA system.

neuroscience↗

bioRxiv2023

Sex differences in pharmacokinetics, central accumulation, and behavioural effects of oral cannabis consumption in male and female C57BL/6 mice.

BackgroundCannabis edibles are an increasingly popular form of cannabis consumption. Oral consumption of cannabis has distinct physiological and behavioural effects than injection or inhalation. An animal model is needed to understand the pharmacokinetics and physiological effects of oral cannabis consumption in rodents as a model for human cannabis edible use. MethodsAdult male and female C57BL/6 mice received a single dose of commercially available cannabis oil (5 mg/kg THC) by oral gavage. At 0.5-, 1-, 2-, 3-, and 6-hours post-exposure, plasma, hippocampus, and adipose tissue was collected for THC, 11-OH-THC, and THC-COOH measures. ResultsWe report delayed time to peak THC and 11-OH-THC concentrations in plasma, brain and adipose tissue, which is consistent with human pharmacokinetics studies. We also found sex differences in the cannabis tetrad: (1) female mice had a delayed hypothermic effect 6 hours post-consumption, which was not present in males; (2) females had stronger catalepsy than males; (3) males were less mobile following cannabis exposure, whereas female mice showed no difference in locomotion but an anxiogenic effect at 3h post exposure; and (4) male mice displayed a longer lasting antinociceptive effect of oral cannabis. ConclusionsOral cannabis consumption is a translationally relevant form of administration that produces similar physiological effects as injection or vaping administration and thus should be considered as a viable approach for examining the physiological effects of cannabis moving forward. Furthermore, given the strong sex differences in metabolism of oral cannabis, these factors should be carefully considered when designing animal studies on the effects of cannabis. Significance statementOral delivery of cannabis oil in mice is a translational model that increases plasma, hippocampal, and adipose cannabinoids. Furthermore, oral cannabis and produces lasting psychoactive effects including sex dependent effects on hypothermia, cataplexy, locomotor activity and nociception.

pharmacology and toxicology↗

bioRxiv2023

Short- and long-term high-fat diet exposure differentially alters phasic and tonic GABAergic signalling onto lateral orbitofrontal pyramidal neurons

The chronic consumption of caloric dense high-fat foods is a major contributor to increased body weight, obesity, and other chronic health conditions. The orbitofrontal cortex (OFC) is critical in guiding decisions about food intake and is altered with diet-induced obesity. Obese rodents have altered morphological and synaptic electrophysiological properties in the lateral orbitofrontal cortex (lOFC). Yet the time course by which exposure to a high-fat diet (HFD) induces these changes is poorly understood. Here male mice are exposed to either short- (7 day) or long-term (90 day) HFD. Long-term HFD exposure increases body weight, and glucose signaling compared to short-term HFD or a standard chow control diet (SCD). Both short and long-term HFD exposure increased the excitability of lOFC pyramidal neurons. However, phasic and tonic GABAergic signalling was differentially altered depending on HFD exposure length, such that tonic GABAergic signaling was decreased with early exposure to the HFD and phasic signaling was changed with long-term diet exposure. Furthermore, alterations in the short-term diet exposure were transient, as removal of the diet restored electrophysiological characteristics similar to mice fed SCD whereas long-term HFD electrophysiological changes were persistent and remained after HFD removal. Finally, we demonstrate that changes in reward devaluation occur early with diet exposure. Together, these results suggest that the duration of HFD exposure differentially alters lOFC function and provides mechanistic insights into the susceptibility of the OFC to impairments in outcome devaluation. Significant statementThis study provides mechanistic insight on the impact of short- and long-term high fat diet (HFD) exposure on GABAergic function in the lateral orbitofrontal cortex (lOFC), a region known to guide decision making. We find short-term HFD exposure induces transient changes in firing and tonic GABA action on lOFC pyramidal neurons, whereas long-term HFD induces obesity and has lasting changes on firing, tonic GABA and inhibitory synaptic transmission onto lOFC neurons. Given that GABAergic signaling in the lOFC can influence decision making around food, these results have important implications in present society as palatable energy dense foods are abundantly available.

neuroscience↗

bioRxiv2021

Activation of LH GABAergic inputs counteracts fasting-induced changes in tVTA/RMTG neurons.

Dopamine neurons in the ventral tegmental area (VTA) are strongly innervated by GABAergic neurons in the tail of the VTA (tVTA), also known as the rostralmedial tegmental nucleus (RMTg). Disinhibition of dopamine neurons through firing of the GABAergic neurons projecting from the lateral hypothalamus (LH) leads to reward seeking and consumption through dopamine release in the nucleus accumbens. VTA dopamine neurons respond to changes in motivational state, yet less is known of whether tVTA/RMTg GABAergic neurons or the LH GABAergic neurons that project to them are also affected by changes in motivational state, such as fasting. An acute 16 h overnight fast decreased the excitability of tVTA/RMTg GABAergic neurons of male and female mice. In addition, fasting decreased synaptic strength at LH GABA to tVTA/RMTg GABAergic synapses, indicated by reduced amplitude of optically evoked currents, decreased readily releasable pool (RRP) size and replenishment. Optical stimulation of LH GABA terminals suppressed evoked action potentials of tVTA/RMTg GABAergic neurons in unfasted mice, but this effect decreased following fasting. Furthermore, during fasting, LH GABA inputs to tVTA/RMTg neurons maintained functional connectivity during depolarization, as depolarization block was reduced following fasting. Taken together, inhibitory synaptic transmission from LH GABA inputs onto tVTA/RMTg GABAergic neurons decreases following fasting, however ability to functionally inhibit tVTA/RMTg GABAergic neurons is preserved, allowing for possible disinhibition of dopamine neurons and subsequent foraging. Key PointsO_LIWhile dopamine neuronal activity changes with motivational state, it is unknown if fasting influences tVTA/RMTg GABAergic neurons, a major inhibitory input to VTA dopamine neurons. C_LIO_LIIn unfasted mice, there were sex differences in inhibitory synaptic transmission onto tVTA/RMTg GABAergic neurons. C_LIO_LIActivation of LH GABAergic neurons decreases firing of tVTA/RMTg GABAergic neurons through a monosynaptic input. C_LIO_LIAn acute fast decreased the excitability of tVTA/RMTg GABAergic neurons. C_LIO_LIAn acute fast decreases inhibitory synaptic transmission of the LH GABA input to tVTA/RMTg GABAergic neurons in both male and female mice. C_LI

neuroscience↗

bioRxiv2021

Pharmacokinetics and Central Accumulation of Delta-9-Tetrahydrocannabinol (THC) and its Bioactive Metabolites are Influenced by Route of Administration and Sex

Up to a third of North Americans over 16 years old report using cannabis in the prior month, most commonly through inhalation. Animal models that reflect human cannabis consumption are critical to study its impacts on brain and behaviour. Nevertheless, most animal studies to date examine effects of cannabis through injection of delta-9-tetrahydrocannabinol (THC; primary psychoactive component of cannabis). THC injections produce markedly different physiological and behavioural effects than inhalation, likely due to distinctive pharmacokinetics of each administration route. The current study directly examined if administration route (injection versus inhalation), with dosing being matched on peak THC blood levels, alters the metabolism of THC, and the central accumulation of THC and its metabolites over time. Adult male and female Sprague-Dawley rats received either a single intraperitoneal injection of THC (2.5 mg/kg) or a single (15 min) session of inhaled exposure to THC distillate (100 mg/mL) vapour. Blood and brains were collected at 15, 30, 60, 90 and 240 minutes post-exposure for analysis of THC and metabolites through mass spectrometry-liquid chromatography. Inhalation results in immediate hypothermia, whereas injection results in delayed hypothermia. Despite achieving comparable peak concentrations of blood THC in both groups, our results indicate higher initial brain THC concentration following inhalation, whereas injection resulted in dramatically higher 11-OH-THC concentrations, a potent THC metabolite, in blood and brain that increased over time. Our results provide evidence that THC and its metabolites exhibit different pharmacokinetic profiles following inhalation versus injection, which could have significant impacts for data interpretation and generalizability. Accordingly, we suggest that translational work in the realm of THC and cannabis strongly consider using inhalation models over those that employ injection. HighlightsO_LIBody temperature as well as blood and brain levels of THC and metabolites differ based on administration route C_LIO_LITHC inhalation results in immediate hypothermia, whereas THC injection results in delayed hypothermia C_LIO_LITHC inhalation results in higher initial brain THC levels than injection C_LIO_LITHC injection results in higher blood & brain 11-OH-THC levels than inhalation C_LIO_LITranslational cannabis work should strongly consider using inhalation over injection C_LI

neuroscience↗

bioRxiv2020

Optogenetic stimulation of lateral hypothalamic orexin/dynorphin inputs in the ventral tegmental area potentiates mesolimbic dopamine neurotransmission and promotes reward-related behaviours

Reward and reinforcement processes are critical for survival and propagation of genes. While numerous brain systems underlie these processes, a cardinal role is ascribed to mesolimbic dopamine. However, ventral tegmental area (VTA) dopamine neurons receive complex innervation and various neuromodulatory factors, including input from lateral hypothalamic (LH) orexin/hypocretin neurons which also express and co-release the neuropeptide, dynorphin. Dynorphin in the VTA induces aversive conditioning through the Kappa opioid receptor (KOR) and decreases dopamine when administered intra-VTA. Exogenous application of orexin or orexin 1 receptor (oxR1) antagonists in the VTA bidirectionally modulates dopamine-driven motivation and reward-seeking behaviours, including the attribution of motivational value to primary rewards and associated conditioned stimuli. However, the effect of endogenous stimulation of LH orexin/dynorphin-containing projections to the VTA and the potential contribution of co-released dynorphin on mesolimbic dopamine and reward related processes remains uncharacterised. We combined optogenetic, electrochemical, and behavioural approaches to examine this. We found that optical stimulation of LH orexin/dynorphin inputs in the VTA potentiates mesolimbic dopamine neurotransmission in the nucleus accumbens (NAc) core, produces real time and conditioned place preference, and increases the food cue-directed orientation in a Pavlovian conditioning procedure. LH orexin/dynorphin potentiation of NAc dopamine release and real time place preference was blocked by an oxR1, but not KOR antagonist. Thus, rewarding effects associated with optical stimulation of LH orexin/dynorphin inputs in the VTA are predominantly driven by orexin rather than dynorphin.

neuroscience↗

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↗