Biology subjects

Heien, M. L.

Publications and source records attributed to Heien, M. L..

3 recordsLinked to original sources

bioRxiv2025

Early intervention with a PACAP lactoside following repetitive mild traumatic brain injury prevents persistent LHb hyperactivity and motivational deficits in male mice

Mild traumatic brain injury (mTBI) often leads to long-lasting mood disorders and motivational deficits, significantly decreasing quality of life. The neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) has known neuroprotective effects and is often deficient in neurological conditions, but its role in preventing mTBI's long-term effects on mood circuits remains unclear. Our previous studies of repetitive closed-head mTBI in murine models found that the lateral habenula (LHb) is a key area for post-injury impairments. These impairments are characterized by mTBI-induced LHb hyperactivity and mood-related behavioral deficits. Here we investigated if a novel PACAP type I receptor (PAC1R) agonist, TES2320, could prevent or treat these long-term mTBI effects. The drug is based on a truncated glycoside analogue of PACAP that is stable and brain penetrant. Using RNAscope, we first found that mTBI caused a persistent and widespread reduction in PACAP mRNA within the LHb, suggesting a possible mTBI-related PACAP signaling deficiency in LHb circuits. We then used two intervention strategies in young adult male mice: an early intervention administered immediately after injury and a late intervention given as a single injection one-month post-injury. One month after injury, we measured LHb activity and self-care grooming motivation. Both early and late PAC1 agonist interventions almost completely normalized the mTBI-induced increases in LHb spontaneous tonic activity and hyperexcitability. However, only the early intervention improved the delayed initiation of grooming seen in mTBI mice. Unfortunately, a single late PAC1R agonist injection not only failed to reverse the grooming delay, but also significantly reduced total grooming behavior 24 hours after treatment. This finding points to a potential behavioral side effect of late PAC1R agonist administration on grooming. Overall, our findings confirm that an early PAC1R agonist intervention effectively prevents mTBI-induced LHb hyperactivity and associated motivational deficits, likely by restoring the persistent PACAP signaling deficiency in the LHb and its related circuits. This preclinical study provides strong evidence that novel PAC1R agonists could be a valuable preventive therapy for mTBI-related depression and anti-reward circuit dysfunction.

neuroscience↗

bioRxiv2023

Antagonism of kappa opioid receptors worsens the development of L-DOPA-induced dyskinesia in a preclinical model of moderate dopamine depletion

Levels of the opioid peptide dynorphin, an endogenous ligand selective for kappa-opioid receptors (KORs), its mRNA and pro-peptide precursors are differentially dysregulated in Parkinsons disease (PD) and following the development of L-DOPA-induced dyskinesia (LID). It remains unclear whether these alterations contribute to the pathophysiological mechanisms underlying PD motor impairment and the subsequent development of LID, or whether they are part of compensatory mechanisms. We sought to investigate nor-BNI, a KOR antagonist, 1) in the dopamine (DA)-depleted PD state, 2) during the development phase of LID, and 3) via measuring of tonic levels of striatal DA. While nor-BNI (3 mg/kg; s.c.) did not lead to functional restoration in the DA-depleted state, it affected the dose-dependent development of abnormal voluntary movements (AIMs) in response to escalating doses of L-DOPA in a rat PD model with a moderate striatal 6-hydroxdopamine (6-OHDA) lesion. We tested five escalating doses of L-DOPA (6, 12, 24, 48, 72 mg/kg; i.p.), and nor-BNI significantly increased the development of AIMs at the 12 and 24 mg/kg L-DOPA doses. However, after reaching the 72 mg/kg L-DOPA, AIMs were not significantly different between control and nor-BNI groups. In summary, while blocking KORs significantly increased the rate of development of LID induced by chronic, escalating doses of L-DOPA in a moderate-lesioned rat PD model, it did not contribute further once the overall severity of LID was established. While we observed an increase of tonic DA levels in the moderately lesioned dorsolateral striatum, there was no tonic DA change following administration of nor-BNI. HighlightsO_LIMild L-DOPA-induced dyskinesia develops in moderately lesioned parkinsonian rats C_LIO_LIIn the moderately-lesioned dorsolateral striatum tonic dopamine is increased C_LIO_LIAntagonizing dynorphin does not affect parkinsonian motor symptoms in rodents C_LIO_LIAntagonizing dynorphin increases rate of development of L-DOPA-induced dyskinesia C_LIO_LITonic dopamine in dorsolateral striatum is unchanged after antagonizing dynorphin C_LI

neuroscience↗

bioRxiv2022

Heterogeneous patterns of ventral tegmental area neuronal activity coordinate nucleus accumbens dopamine release

Dopamine release in the ventral striatum is fundamental to adaptive appetitive behavior. Frustratingly, technological, and methodological hurdles have limited the investigation of the mechanisms that drive phasic dopamine release. Although dopamine neuron activation in the ventral tegmental area (VTA) surely results in dopamine release, how populations of these neurons coordinate their activities in time to modulate the temporal pattern of release remains unclear. Additionally, burgeoning evidence suggests that control over striatal dopamine release is not solely regulated by the burst firing of VTA neurons or even cell-body activation of these neurons. Here, we recorded VTA neurons while simultaneously monitoring pharmacologically induced phasic dopamine release events in the ventral striatum (nucleus accumbens core) of anesthetized rats. On average, dopaminergic and non-dopaminergic neurons increased activity at the time of the onset of release and decreased at the time of peak release; however, the tuning of individual VTA neurons to dopamine release was notably heterogenous, with subsets of neurons responding prior to release, at release onset, or during release. Other neurons were notably silent during release but active otherwise. Interestingly, both putative dopaminergic and non-dopaminergic neurons expressed this temporally heterogeneous response pattern. Furthermore, the firing activity of dopaminergic, but not non-dopaminergic neurons, correlated with the magnitude of dopamine release. These data suggest that populations of VTA neurons become active at distinct times of a dopamine release event to sculpt the temporal pattern of release.

neuroscience↗