scholarly journals Cell specific photoswitchable agonist for reversible control of endogenous dopamine receptors

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Prashant Donthamsetti ◽  
Nils Winter ◽  
Adam Hoagland ◽  
Cherise Stanley ◽  
Meike Visel ◽  
...  
Keyword(s):  
Dopamine Receptors ◽  
Complex Dynamics ◽  
Receptor Subtypes ◽  
Medium Spiny Neurons ◽  
Neuronal Function ◽  
Cell Type Specificity ◽  
Movement Initiation ◽  
Endogenous Dopamine ◽  
Spiny Neurons

AbstractDopamine controls diverse behaviors and their dysregulation contributes to many disorders. Our ability to understand and manipulate the function of dopamine is limited by the heterogenous nature of dopaminergic projections, the diversity of neurons that are regulated by dopamine, the varying distribution of the five dopamine receptors (DARs), and the complex dynamics of dopamine release. In order to improve our ability to specifically modulate distinct DARs, here we develop a photo-pharmacological strategy using a Membrane anchored Photoswitchable orthogonal remotely tethered agonist for the Dopamine receptor (MP-D). Our design selectively targets D1R/D5R receptor subtypes, most potently D1R (MP-D1ago), as shown in HEK293T cells. In vivo, we targeted dorsal striatal medium spiny neurons where the photo-activation of MP-D1ago increased movement initiation, although further work is required to assess the effects of MP-D1ago on neuronal function. Our method combines ligand and cell type-specificity with temporally precise and reversible activation of D1R to control specific aspects of movement. Our results provide a template for analyzing dopamine receptors.

Dopamine facilitates dendritic spine formation by cultured striatal medium spiny neurons through both D1 and D2 dopamine receptors

2013 ◽  
Vol 67 ◽  
pp. 432-443 ◽  
Author(s):  
Caroline Fasano ◽  
Marie-Josée Bourque ◽  
Gabriel Lapointe ◽  
Damiana Leo ◽  
Dominic Thibault ◽  
...  
Keyword(s):  
Dopamine Receptors ◽  
Dendritic Spine ◽  
Medium Spiny Neurons ◽  
D2 Dopamine Receptors ◽  
Spine Formation ◽  
Spiny Neurons

scholarly journals Binge Alcohol Drinking Alters Synaptic Processing of Executive and Emotional Information in Core Nucleus Accumbens Medium Spiny Neurons

2021 ◽  
Vol 15 ◽  
Author(s):  
Jenya Kolpakova ◽  
Vincent van der Vinne ◽  
Pablo Giménez-Gómez ◽  
Timmy Le ◽  
In-Jee You ◽  
...  
Keyword(s):  
Nucleus Accumbens ◽  
Alcohol Drinking ◽  
Drugs Of Abuse ◽  
Alcohol Exposure ◽  
Medium Spiny Neurons ◽  
Dependent Manner ◽  
Emotional Information ◽  
Core Nucleus ◽  
Spiny Neurons

The nucleus accumbens (NAc) is a forebrain region mediating the positive-reinforcing properties of drugs of abuse, including alcohol. It receives glutamatergic projections from multiple forebrain and limbic regions such as the prefrontal cortex (PFCx) and basolateral amygdala (BLA), respectively. However, it is unknown how NAc medium spiny neurons (MSNs) integrate PFCx and BLA inputs, and how this integration is affected by alcohol exposure. Because progress has been hampered by the inability to independently stimulate different pathways, we implemented a dual wavelength optogenetic approach to selectively and independently stimulate PFCx and BLA NAc inputs within the same brain slice. This approach functionally demonstrates that PFCx and BLA inputs synapse onto the same MSNs where they reciprocally inhibit each other pre-synaptically in a strict time-dependent manner. In alcohol-naïve mice, this temporal gating of BLA-inputs by PFCx afferents is stronger than the reverse, revealing that MSNs prioritize high-order executive processes information from the PFCx. Importantly, binge alcohol drinking alters this reciprocal inhibition by unilaterally strengthening BLA inhibition of PFCx inputs. In line with this observation, we demonstrate that in vivo optogenetic stimulation of the BLA, but not PFCx, blocks binge alcohol drinking escalation in mice. Overall, our results identify NAc MSNs as a key integrator of executive and emotional information and show that this integration is dysregulated during binge alcohol drinking.

scholarly journals Medium spiny neurons activity reveals the discrete segregation of mouse dorsal striatum

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Javier Alegre-Cortés ◽  
María Sáez ◽  
Roberto Montanari ◽  
Ramon Reig
Keyword(s):  
Dorsal Striatum ◽  
Medium Spiny Neurons ◽  
Extracellular Recordings ◽  
Electrophysiological Properties ◽  
Spiny Neurons ◽  
Behavioral Studies ◽  
Sensory Activity ◽  
Fast Oscillations ◽  
Anatomical Evidence

Behavioral studies differentiate the rodent dorsal striatum (DS) into lateral and medial regions; however, anatomical evidence suggests that it is a unified structure. To understand striatal dynamics and basal ganglia functions, it is essential to clarify the circuitry that supports this behavioral-based segregation. Here, we show that the mouse DS is made of two non-overlapping functional circuits divided by a boundary. Combining in vivo optopatch-clamp and extracellular recordings of spontaneous and evoked sensory activity, we demonstrate different coupling of lateral and medial striatum to the cortex together with an independent integration of the spontaneous activity, due to particular corticostriatal connectivity and local attributes of each region. Additionally, we show differences in slow and fast oscillations and in the electrophysiological properties between striatonigral and striatopallidal neurons. In summary, these results demonstrate that the rodent DS is segregated in two neuronal circuits, in homology with the caudate and putamen nuclei of primates.

scholarly journals Injection with Toxoplasma gondii protein affects neuron health and survival

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Oscar A Mendez ◽  
Emiliano Flores Machado ◽  
Jing Lu ◽  
Anita Koshy
Keyword(s):  
Toxoplasma Gondii ◽  
Single Neuron ◽  
Latent Infection ◽  
Medium Spiny Neurons ◽  
Patch Clamping ◽  
Spiny Neurons ◽  
The Brain ◽  
Mapping Program

Toxoplasma gondii is an intracellular parasite that causes a long-term latent infection of neurons. Using a custom MATLAB-based mapping program in combination with a mouse model that allows us to permanently mark neurons injected with parasite proteins, we found that Toxoplasma-injected neurons (TINs) are heterogeneously distributed in the brain, primarily localizing to the cortex followed by the striatum. In addition, we determined that cortical TINs are commonly (>50%) excitatory neurons (FoxP2+) and that striatal TINs are often (>65%) medium spiny neurons (MSNs) (FoxP2+). By performing single neuron patch-clamping on striatal TINs and neighboring uninfected MSNs, we discovered that TINs have highly aberrant electrophysiology. As approximately 90% of TINs will die by 8 weeks post-infection, this abnormal physiology suggests that injection with Toxoplasma protein— either directly or indirectly— affects neuronal health and survival. Collectively, these data offer the first insights into which neurons interact with Toxoplasma and how these interactions alter neuron physiology in vivo.

scholarly journals Neuronal signature of an antipsychotic response

2020 ◽  
Author(s):  
Jeffrey Parrilla-Carrero ◽  
Anna Kruyer ◽  
Reda M. Chalhoub ◽  
Courtney Powell ◽  
Shanna Resendez ◽  
...  
Keyword(s):  
D2 Receptor ◽  
Symptom Improvement ◽  
Medium Spiny Neurons ◽  
Principal Mechanism ◽  
Spiny Neurons ◽  
Nmda Channel ◽  
Resolution Imaging ◽  
The Impact ◽  
The Brain

Abstract D2 receptor blockade has been cited as a principal mechanism of action of all antipsychotic medications, but is poorly predictive of symptom improvement or neurophysiological responses recorded using human brain imaging. A potential hurdle in interpreting such human imaging studies arises from the inability to distinguish activity within neuronal subcircuits. We used single cell resolution imaging to record activity in distinct populations of medium spiny neurons in vivo within the mouse ventral striatum, a structure associated with schizophrenia symptoms and antipsychotic therapeutic efficacy. While we expected the antipsychotic haloperidol to excite D2 receptor expressing neurons, we report a strong cellular depression mediated by the hypofunctional NMDA channel, which may be mediated in part by the action of haloperidol on the sigma1 receptor. Altogether, the impact of haloperidol on Ca2+ events in D2 receptor expressing neurons predicted psychomotor inhibition. Our results elucidate mechanisms by which antipsychotics act rapidly in the brain to impact psychomotor outputs.

Kv1.2-Containing K+ Channels Regulate Subthreshold Excitability of Striatal Medium Spiny Neurons

2004 ◽  
Vol 91 (3) ◽  
pp. 1337-1349 ◽  
Author(s):  
Weixing Shen ◽  
Salvador Hernandez-Lopez ◽  
Tatiana Tkatch ◽  
Joshua E. Held ◽  
D. James Surmeier
Keyword(s):  
State Transitions ◽  
Medium Spiny Neurons ◽  
Rt Pcr ◽  
High Affinity ◽  
Spiny Neurons ◽  
Low Threshold ◽  
Rapid Activation ◽  
Repetitive Discharge ◽  
Spike Latency

A slowly inactivating, low-threshold K+ current has been implicated in the regulation of state transitions and repetitive activity in striatal medium spiny neurons. However, the molecular identity of the channels underlying this current and their biophysical properties remain to be clearly determined. Because previous work had suggested this current arose from Kv1 family channels, high-affinity toxins for this family were tested for their ability to block whole cell K+ currents activated by depolarization of acutely isolated neurons. α-Dendrotoxin, which blocks channels containing Kv1.1, Kv1.2, or Kv1.6 subunits, decreased currents evoked by depolarization. Three other Kv1 family toxins that lack a high affinity for Kv1.2 subunits, r-agitoxin-2, dendrotoxin-K, and r-margatoxin, failed to significantly reduce currents, implicating channels with Kv1.2 subunits. RT-PCR results confirmed the expression of Kv1.2 mRNA in identified medium spiny neurons. Currents attributable to Kv1.2 channels activated rapidly, inactivated slowly, and recovered from inactivation slowly. In the subthreshold range (ca. -60 mV), these currents accounted for as much as 50% of the depolarization-activated K+ current. Moreover, their rapid activation and relatively slow deactivation suggested that they contribute to spike afterpotentials regulating repetitive discharge. This inference was confirmed in current-clamp recordings from medium spiny neurons in the slice preparation where Kv1.2 blockade reduced first-spike latency and increased discharge frequency evoked from hyperpolarized membrane potentials resembling the “down-state” found in vivo. These studies establish a clear functional role for somato-dendritic Kv1.2 channels in the regulation of state transitions and repetitive discharge in striatal medium spiny neurons.

scholarly journals Conditional, inducible gene silencing in dopamine neurons reveals a sex-specific role for Rit2 GTPase in acute cocaine response and striatal function

2019 ◽  
Author(s):  
Carolyn G. Sweeney ◽  
Patrick J. Kearney ◽  
Rita R. Fagan ◽  
Lindsey A. Smith ◽  
Nicholas C. Bolden ◽  
...  
Keyword(s):  
Ventral Striatum ◽  
Surface Expression ◽  
Dopamine Neurons ◽  
Medium Spiny Neurons ◽  
Protein Levels ◽  
Spiny Neurons ◽  
Males And Females ◽  
Striatal Function ◽  
Inducible Gene

AbstractDopamine (DA) signaling is critical for movement, motivation, and addictive behavior. The neuronal GTPase, Rit2, is enriched in DA neurons (DANs), binds directly to the DA transporter (DAT), and is implicated in several DA-related neuropsychiatric disorders. However, it remains unknown whether Rit2 plays a role in either DAergic signaling and/or DA-dependent behaviors. Here, we leveraged the TET-OFF system to conditionally silence Rit2 in Pitx3IRES2-tTA mouse DANs. Following DAergic Rit2 knockdown (Rit2-KD), mice displayed an anxiolytic phenotype, with no change in baseline locomotion. Further, males exhibited increased acute cocaine sensitivity, whereas DAergic Rit2-KD suppressed acute cocaine sensitivity in females. DAergic Rit2-KD did not affect presynaptic TH and DAT protein levels in females, nor was TH was affected in males; however, DAT was significantly diminished in males. Paradoxically, despite decreased DAT levels in males, striatal DA uptake was enhanced, but was not due to enhanced DAT surface expression in either dorsal or ventral striatum. Finally, patch recordings in nucleus accumbens (NAcc) medium spiny neurons (MSNs) revealed reciprocal changes in spontaneous EPSP (sEPSP) frequency in male and female D1+ and D2+ MSNs following DAergic Rit2-KD. In males, sEPSP frequency was decreased in D1+, but not D2+, MSNs, whereas in females sEPSP frequency decreased in D2+, but not D1+, MSNs. Moreover, DAergic Rit2-KD abolished the ability of cocaine to reduce sEPSP frequency in D1+, but not D2+, male MSNs. Taken together, our studies are among the first to acheive AAV-mediated, conditional and inducible DAergic knockdown in vivo. Importantly, our results provide the first evidence that DAergic Rit2 expression differentially impacts striatal function and DA-dependent behaviors in males and females.

scholarly journals Inhibitory ultrapotent chemogenetics activate dopamine D1 receptor-expressing medium spiny neurons

2020 ◽  
Author(s):  
Stephanie C. Gantz ◽  
Maria M. Ortiz ◽  
Andrew J. Belilos ◽  
Khaled Moussawi
Keyword(s):  
Brain Slices ◽  
Reversal Potential ◽  
Cell Types ◽  
Receptor Activation ◽  
Dopamine D1 Receptor ◽  
D1 Receptor ◽  
Medium Spiny Neurons ◽  
Inhibitory Function ◽  
Spiny Neurons

SUMMARYUltrapotent chemogenetics, including the chloride-permeable inhibitory PSAM4-GlyR receptor, were recently proposed as a powerful strategy to selectively control neuronal activity in awake, behaving animals. We aimed to validate the inhibitory function of PSAM4-GlyR in dopamine D1 receptor-expressing medium spiny neurons (D1-MSNs) in the ventral striatum. Activation of PSAM4-GlyR with the uPSEM792 ligand enhanced rather than suppressed the activity of D1-MSNs in vivo as indicated by increased c-fos expression in D1-MSNs. Whole-cell recordings in mouse brain slices showed that activation of PSAM4-GlyR did not inhibit firing of action potentials in D1-MSNs. Activation of PSAM4-GlyR depolarized D1-MSNs, attenuated GABAergic inhibition, and shifted the reversal potential of PSAM4-GlyR current to more depolarized potentials, perpetuating the depolarizing effect of receptor activation. The data show that ‘inhibitory’ PSAM4-GlyR chemogenetics may actually activate certain cell types, and highlight the pitfalls of utilizing chloride conductances to inhibit neurons.

Sign in / Sign up

Export Citation Format

Share Document