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.

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 Error-related Signaling in Nucleus Accumbens D2 Receptor-expressing Neurons Guides Avoidance-based Goal-directed Behavior

2022 ◽  
Author(s):  
Tadaaki Nishioka ◽  
Tom Macpherson ◽  
Kosuke Hamaguchi ◽  
Takatoshi Hikida
Keyword(s):  
Nucleus Accumbens ◽  
Behavioral Control ◽  
D2 Receptor ◽  
Environmental Cues ◽  
Medium Spiny Neurons ◽  
Spiny Neurons ◽  
Cell Type Specific ◽  
Goal Directed Behavior

Abstract Learnt associations between environmental cues and the outcomes they predict (cue-outcome associations) play a major role in behavioral control, guiding not only which responses we should perform, but also which we should avoid, in order to achieve a specific goal. The encoding of such cue-outcome associations, as well as the performance of cue-guided goal-directed behavior, is thought to involve dopamine D1 and D2 receptor-expressing medium spiny neurons (D1-/D2-MSNs) of the nucleus accumbens (NAc). Here, using a visual discrimination task in mice, we assessed the role of NAc D1-/D2-MSNs in cue-guided goal-directed avoidance of inappropriate responding. Cell-type specific neuronal silencing and in-vivo imaging revealed NAc D2-MSNs to selectively contribute to cue-guided avoidance behavior, with activation of NAc D2-MSNs following response error playing an important role in optimizing future goal-directed behavior. Our findings indicate that error-signaling by NAc D2-MSNs underlies the ability to use environmental cues to avoid inappropriate behavior.

Effects of CSF Properties on Brain Response Under Impact Loading

2009 ◽  
Author(s):  
M. S. Chafi ◽  
V. Dirisala ◽  
G. Karami ◽  
M. Ziejewski
Keyword(s):  
Human Head ◽  
Brain Response ◽  
Pia Mater ◽  
Mechanical Shocks ◽  
The Central Nervous System ◽  
Simultaneous Loading ◽  
The Impact ◽  
Impact Experiments ◽  
The Brain

In the central nervous system, the subarachnoid space is the interval between the arachnoid membrane and the pia mater. It is filled with a clear, watery liquid called cerebrospinal fluid (CSF). The CSF buffers the brain against mechanical shocks and creates buoyancy to protect it from the forces of gravity. The relative motion of the brain due to a simultaneous loading is caused because the skull and brain have different densities and the CSF surrounds the brain. The impact experiments are usually carried out on cadavers with no CSF included because of the autolysis. Even in the cadaveric head impact experiments by Hardy et al. [1], where the specimens are repressurized using artificial CSF, this is not known how far this can replicate the real functionality of CSF. With such motivation, a special interest lies on how to model this feature in a finite element (FE) modeling of the human head because it is questionable if one uses in vivo CSF properties (i.e. bulk modulus of 2.19 GPa) to validate a FE human head against cadaveric experimental data.

scholarly journals Toxoplasma gondii injected neurons localize to the cortex and striatum and have altered firing

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

AbstractToxoplasma 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. Using immunofluorescence co-localization assays, we determined that cortical TINs are commonly (>50%) excitatory neurons (FoxP2+) and that striatal TINs are often (>65%) medium spiny neurons (MSNs) (FoxP2+). As MSNs have highly characterized electrophysiology, we used ex vivo slices from infected mice to perform single neuron patch-clamping on striatal TINs and neighboring uninfected MSNs (bystander MSNs). These studies demonstrated that TINs have highly abnormal electrophysiology, while the electrophysiology of bystander MSNs was akin to that of MSNs from uninfected mice. Collectively, these data offer new neuroanatomic and electrophysiologic insights into CNS toxoplasmosis.

scholarly journals Microglia motility depends on neuronal activity and promotes structural plasticity in the hippocampus

2019 ◽  
Author(s):  
Felix C. Nebeling ◽  
Stefanie Poll ◽  
Lena C. Schmid ◽  
Manuel Mittag ◽  
Julia Steffen ◽  
...  
Keyword(s):  
Neuronal Activity ◽  
Dendritic Spines ◽  
Synapse Formation ◽  
Brain Parenchyma ◽  
Two Photon ◽  
Contact Rates ◽  
Health And Disease ◽  
The Impact ◽  
The Brain

AbstractMicroglia, the resident immune cells of the brain, play a complex role in health and disease. They actively survey the brain parenchyma by physically interacting with other cells and structurally shaping the brain. Yet, the mechanisms underlying microglia motility and their significance for synapse stability, especially during adulthood, remain widely unresolved. Here we investigated the impact of neuronal activity on microglia motility and its implication for synapse formation and survival. We used repetitive two-photon in vivo imaging in the hippocampus of awake mice to simultaneously study microglia motility and their interaction with synapses. We found that microglia process motility depended on neuronal activity. Simultaneously, more dendritic spines emerged in awake compared to anesthetized mice. Interestingly, microglia contact rates with individual dendritic spines were associated with their stability. These results suggest that microglia are not only sensing neuronal activity, but participate in synaptic rewiring of the hippocampus during adulthood, which has profound relevance for learning and memory processes.

scholarly journals Methylmercury Epigenetics

Toxics ◽  
2019 ◽  
Vol 7 (4) ◽  
pp. 56 ◽  
Author(s):  
Megan Culbreth ◽  
Michael Aschner
Keyword(s):  
Dna Methylation ◽  
Mirna Expression ◽  
Epigenetic Modifications ◽  
Nervous System Development ◽  
Gene Promoters ◽  
Toxic Response ◽  
The Impact ◽  
The Brain

Methylmercury (MeHg) has conventionally been investigated for effects on nervous system development. As such, epigenetic modifications have become an attractive mechanistic target, and research on MeHg and epigenetics has rapidly expanded in the past decade. Although, these inquiries are a recent advance in the field, much has been learned in regards to MeHg-induced epigenetic modifications, particularly in the brain. In vitro and in vivo controlled exposure studies illustrate that MeHg effects microRNA (miRNA) expression, histone modifications, and DNA methylation both globally and at individual genes. Moreover, some effects are transgenerationally inherited, as organisms not directly exposed to MeHg exhibited biological and behavioral alterations. miRNA expression generally appears to be downregulated consequent to exposure. Further, global histone acetylation also seems to be reduced, persist at distinct gene promoters, and is contemporaneous with enhanced histone methylation. Moreover, global DNA methylation appears to decrease in brain-derived tissues, but not in the liver; however, selected individual genes in the brain are hypermethylated. Human epidemiological studies have also identified hypo- or hypermethylated individual genes, which correlated with MeHg exposure in distinct populations. Intriguingly, several observed epigenetic modifications can be correlated with known mechanisms of MeHg toxicity. Despite this knowledge, however, the functional consequences of these modifications are not entirely evident. Additional research will be necessary to fully comprehend MeHg-induced epigenetic modifications and the impact on the toxic response.

scholarly journals Cocaine effects on mouse incentive-learning and human addiction are linked to α2 subunit-containing GABAA receptors

2010 ◽  
Vol 107 (5) ◽  
pp. 2289-2294 ◽  
Author(s):  
Claire I. Dixon ◽  
Hannah V. Morris ◽  
Gerome Breen ◽  
Sylvane Desrivieres ◽  
Sarah Jugurnauth ◽  
...  
Keyword(s):  
Behavioral Sensitization ◽  
Binding Pocket ◽  
Receptor Subtype ◽  
Medium Spiny Neurons ◽  
Gabaergic Neurotransmission ◽  
Spiny Neurons ◽  
Benzodiazepine Binding ◽  
Necessary And Sufficient ◽  
The Brain

Because GABAA receptors containing α2 subunits are highly represented in areas of the brain, such as nucleus accumbens (NAcc), frontal cortex, and amygdala, regions intimately involved in signaling motivation and reward, we hypothesized that manipulations of this receptor subtype would influence processing of rewards. Voltage-clamp recordings from NAcc medium spiny neurons of mice with α2 gene deletion showed reduced synaptic GABAA receptor-mediated responses. Behaviorally, the deletion abolished cocaine’s ability to potentiate behaviors conditioned to rewards (conditioned reinforcement), and to support behavioral sensitization. In mice with a point mutation in the benzodiazepine binding pocket of α2-GABAA receptors (α2H101R), GABAergic neurotransmission in medium spiny neurons was identical to that of WT (i.e., the mutation was silent), but importantly, receptor function was now facilitated by the atypical benzodiazepine Ro 15-4513 (ethyl 8-amido-5,6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylate). In α2H101R, but not WT mice, Ro 15-4513 administered directly into the NAcc-stimulated locomotor activity, and when given systemically and repeatedly, induced behavioral sensitization. These data indicate that activation of α2−GABAA receptors (most likely in NAcc) is both necessary and sufficient for behavioral sensitization. Consistent with a role of these receptors in addiction, we found specific markers and haplotypes of the GABRA2 gene to be associated with human cocaine addiction.

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.

Sign in / Sign up

Export Citation Format

Share Document