Biology subjects

Beckstead, M. J.

Publications and source records attributed to Beckstead, M. J..

4 recordsLinked to original sources

bioRxiv2019

Retrograde neurotensin release from dopamine neurons drives long-term depression of substantia nigra dopamine signaling

Midbrain dopamine neurons play central roles in reward learning and motivated behavior, and inhibition at somatodendritic dopamine D2 receptor (D2R) synapses blunts psychostimulant reinforcement. Release of the neuropeptide neurotensin in the midbrain increases following methamphetamine exposure and induces long-term depression of D2R synaptic currents (LTDDA), however the source of neurotensin that drives LTDDA is not known. Here we show that LTDDA is driven by neurotensin released by dopamine neurons. Optogenetic stimulation of dopamine neurons was sufficient to induce LTDDA in the substantia nigra, but not the ventral tegmental area, and was dependent on neurotensin receptors, postsynaptic calcium, and vacuolar-type H+-ATPase activity in the postsynaptic cell. Further, LTDDA was enhanced in mice that had self-administered methamphetamine. These findings reveal a novel form of signaling between dopamine neurons involving release of the peptide neurotensin, which may act as a feed forward mechanism to increase dopamine neuron excitability and methamphetamine self-administration.

neuroscience↗

bioRxiv2019

Neurotensin receptor 1 deletion suppresses methamphetamine self-administration and the associated reduction in dopamine cell firing

We previously reported that pharmacological blockade of neurotensin receptors in the ventral tegmental area (VTA) decreases methamphetamine (METH) self-administration in mice. Here we explored the consequences of genetic deletion of neurotensin receptor 1 (NtsR1) in METH self-administration and VTA dopamine neuron firing activity. We implanted mice with an indwelling jugular catheter and trained them to nose-poke for intravenous infusions of METH. Mice with NtsR1 deletion (KO) acquired selfadministration similar to wildtype (WT) and heterozygous (HET) littermates. However, in NtsR1 KO and HET mice, METH intake and motivated METH seeking decreased when the response requirement was increased to a fixed ratio 3 and when mice were tested on a progressive ratio protocol. After completion of METH self-administration, single cell in vivo extracellular recordings of dopamine firing activity in the VTA were obtained in anesthetized mice. In WT METH-experienced mice, dopamine cell firing frequency dramatically decreases compared to WT drug-naive mice. NtsR1 KO and HET mice did not exhibit this decline of dopamine cell firing activity after prolonged METH selfadministration. We also observed an increase in population activity following METH selfadministration that was strongest in the WT group. Our results suggest a role for NtsR1 in METH-seeking behavior, and ablation of NtsR1 receptors prevents the detrimental effects of prolonged METH self-administration on VTA dopamine cell firing frequency.

neuroscience↗

bioRxiv2019

Female mice are resilient to age-related decline of substantia nigra dopamine neuron firing parameters

The degeneration of substantia nigra (SN) dopamine neurons is a central feature in the pathology associated with Parkinsons disease, which is characterized by progressive loss of motor and cognitive functions. The largest risk factors for Parkinsons disease are age and sex; most cases occur after age 60 and males have nearly twice the incidence as females. While much research in Parkinsons has focused on the mechanisms underlying dopamine neuron degeneration, very little work has considered the influence of these two risk factors to disease risk and presentation. In this work, we performed whole cell patch clamp recordings in brain slices to study the alterations in intrinsic firing properties of single dopamine neurons in C57BL/6 mice across ages and between sexes. We observed a progressive decline in dopamine neuron firing activity in males by 18 months of age, while dopamine neurons from females remained largely unaffected. A semiquantitative analysis of midbrain dopamine neuron populations revealed a slight decrease only in substantia nigra dopamine neurons in males, while females did not change. This was also accompanied by increases in the expression of genes that have been linked to Parkinsons including PTEN-induced kinase 1 (PINK1) in both males and females, and the ubiquitin ligase parkin, primarily in the substantia nigra of males. These impairments in dopamine neuron function in males may represent a vulnerability to further insults that could predispose these cells to neurodegenerative diseases such as in Parkinsons.

neuroscience↗

bioRxiv2019

Repeated treatment with cocaine or methamphetamine increases CRF2 and decreases astrocytic markers in the ventral tegmental area and substantia nigra

Dopamine neurons in the substantia nigra (SN) and ventral tegmental area (VTA) play a crucial role in the reinforcing properties of abused drugs including methamphetamine and cocaine. Evidence also suggests the involvement of non-dopaminergic transmitters, including glutamate and the stress-related peptide corticotropin-releasing factor (CRF), on the chronic effects of psychostimulants in the SN/VTA. Astrocytes express a variety of membrane-bound neurotransmitter receptors and transporters which influence neurotransmission in the SN/VTA. CRF2 activity in the VTA is important for stress-induced relapse and drug-seeking behavior, but the localization of its effects are not completely understood. Here we used immunofluorescence to identify the effect of methamphetamine and cocaine administration on astrocytes, the glial glutamate transporter GLAST, and CRF2 in the SN/VTA. We treated adult male mice with i.p. injections of methamphetamine (3 mg/kg), cocaine (10 mg/kg), or saline for 12 days. Coronal brain sections were processed for immunofluorescence using S100{beta} (marker for astrocytes), glial-specific glutamate/aspartate transporters (GLAST), and CRF2. The results showed a significant decrease in GLAST immunofluorescence in brains of mice treated with cocaine or methamphetamine compared to saline. In addition, we observed increased labelling of CRF2 in drug treated groups, a decrease in the number of S100{beta} positive cells, and an increase in co-staining of these two markers. Our results suggest that administration of either methamphetamine or cocaine decreases astrocytic markers and increases immunoreactivity for CRF2 in the VTA, an effect that is most pronounced in S100{beta} positive cells.

neuroscience↗