Potentiation of glutamatergic synaptic transmission onto lateral habenula neurons following early life stress and intravenous morphine self‐administration in rats

Abstract

Early life stress presents an important risk factor for drug addiction and comorbid depression and anxiety through persistent effects on the mesolimbic dopamine pathways. Using an early life stress model for child neglect (a single 24 h episode of maternal deprivation, MD) in rats, recent published works from our lab show that MD induces dysfunction in the ventral tegmental area and its negative controller, the lateral habenula (LHb). MD‐induced potentiation of glutamatergic synaptic transmission onto LHb neurons shifts the coordination of excitation/inhibition (E/I) balance towards excitation, resulting in an increase in the overall spontaneous neuronal activity with elevation in bursting and tonic firing, and in the intrinsic excitability of LHb neurons in early adolescent male rats. Here, we explored how MD affects intravenous morphine self‐administration (MSA) acquisition and sucrose preference as well as glutamatergic synaptic function in LHb neurons of adult male rats self‐administering morphine. We found that MD‐induced increases in LHb neuronal and glutamatergic synaptic activity and E/I ratio persisted into adulthood. Moreover, MD significantly reduced morphine intake, triggered anhedonia‐like behaviour in the sucrose preference test and was associated with persistent glutamatergic potentiation 24 h after the last MSA session. MSA also altered the decay time kinetics of α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA) receptor (AMPAR) currents in LHb neurons of control rats during this time period. Our data highlight that early life stress‐induced glutamatergic plasticity in LHb may dampen the positive reinforcing and motivational properties of both natural rewards and opioids, and may contribute to the development of anhedonia and dysphoric states associated with opioids.

Blast-Induced Mild Traumatic Brain Injury Alterations of Corticotropin-Releasing Factor Neuronal Activity in the Mouse Hypothalamic Paraventricular Nucleus

“…Given that the more negative RMPs in the mouse PVN are reported in CRFR1 neurons within the dPVN that are exclusively GABAergic and are rarely found to be CRF positive (Jiang et al, 2018 ), we believe that the CRF neurons recorded here are a different population that exhibit more positive RMPs. Our observation of unusually more depolarized RMPs for CRF neurons are also consistent with what we have observed in other spontaneously active neurons when firing in tonic mode such as lateral habenula or ventral tegmental area dopamine neurons (Shepard et al, 2020 ; Langlois et al, 2021 ). However, we acknowledge that our measurements of RMPs are always made immediately after achieving whole-cell patch configuration in current clamp recordings while the evaluation of true RMPs of spontaneously active neurons requires spike silencing.…”

Lateral Habenula Beyond Avoidance: Roles in Stress, Memory, and Decision-Making With Implications for Psychiatric Disorders

“…Prominent ELS rodent and primate models employ early disruptions in mother-infant relationship such as a single 24 h maternal deprivation (MD), repeated daily maternal separation (MS), and limited bedding and nesting (LBN) (Macrì et al, 2007;Nishi et al, 2014;Shepard et al, 2018a;Okhuarobo et al, 2020). Although these ELS models may not reflect all types of early adverse experiences, they are associated with persistent depressive-and anhedonia-like behaviors (Tchenio et al, 2017;Authement et al, 2018;Bolton et al, 2018a;Shepard et al, 2018b;Simmons et al, 2020) and altered drug reward (Bolton et al, 2018b;Okhuarobo et al, 2020;Langlois et al, 2021;Levis et al, 2021) suggesting the translational validity of these models for child neglect. However, it should be noted that not all animals that experience ELS develop stress psychopathology or substance use disorders later in life which is also the case for children exposed to adversity (Kalinichev et al, 2002;Moffett et al, 2006;Ordoñes Sanchez et al, 2021).…”

“…Several neural pathways and neurobiological mechanisms such as the hypothalamic-pituitary-adrenal (HPA) axis and extrahypothalamic corticotropin-releasing factor (CRF) circuits have been identified by which ELS may increase the risk for mood dysregulation, stress-related disorders and addiction (Nemeroff, 2016). Emerging evidence now suggests that ELS-induced alterations of reward-and stress-related brain regions such as ventral tegmental area (VTA), amygdala, nucleus accumbens, prefrontal cortex and LHb may underlie the increased risk for ELS-induced psychopathology (Authement et al, 2015(Authement et al, , 2018Peña et al, 2017Peña et al, , 2019Tchenio et al, 2017;Bolton et al, 2018a;Simmons et al, 2020;Langlois et al, 2021;Oh et al, 2021;Shepard and Nugent, 2021). Specifically, recent studies provided compelling evidence that the LHb is a critical converging brain region for ELS-induced dysregulation of reward circuits (Tchenio et al, 2017;Authement et al, 2018;Bolton et al, 2018b;Simmons et al, 2020).…”

“…Such a contribution appears to rely on the integration and signaling of cognitive, motivational/emotional, and behavioral state information (Sutherland, 1982;Chastrette et al, 1991;Nair et al, 2013;Mendoza, 2017;Shepard and Nugent, 2021). For example, LHb responds to positive and negative choice outcomes (Matsumoto and Hikosaka, 2009;Li et al, 2019), the generation of prediction error signals (Hong and Hikosaka, 2013;Tian and Uchida, 2015), changes in motivational and physiological states [e.g., stress, time of day, etc., (Shepard et al, 2018b;Salaberry et al, 2019;Langlois et al, 2021)], and changes in behavioral state (Baker et al, 2015;Nuno-Perez et al, 2018;Lecca et al, 2020).…”

A diencephalic circuit for opioid analgesia but not positive reinforcement

“…Because LHb neurons generally fire more in response to noxious stimuli, and optogenetic stimulation of various glutamatergic inputs to the LHb is uniformly aversive 27,29,30,48,49 , we hypothesized that a glutamatergic input to the LHb transmits the pain signal. Further, aversive stressors lead to an increase in the ratio of excitatory glutamatergic to inhibitory GABAergic in synaptic input to LHb neurons [48][49][50] , and restoration of this ratio is associated with relief of aversive states such as foot shock-induced learned helplessness 49 and cocaine withdrawal 48 . Therefore, a pharmacological manipulation that decreases the excitatory drive onto LHb neurons should also relieve aversive states.…”