Acute social defeat during adolescence promotes long-lasting aggression through activation of the medial amygdala.

Traumatic stress, particularly during critical developmental periods such as adolescence, has been strongly linked to an increased propensity and severity of aggression. Existing literature underscores that being a victim of abuse can exacerbate aggressive behaviors, with the amygdala playing a pivotal role in mediating these effects. Historically, animal models have demonstrated that traumatic stressors can increase attack behavior, implicating various amygdala nuclei.

Visualizing traumatic stress-induced structural plasticity in a medial amygdala pathway using mGRASP.

Traumatic stress has been shown to contribute to persistent behavioral changes, yet the underlying neural pathways are not fully explored. Structural plasticity, a form of long-lasting neural adaptability, offers a plausible mechanism. To scrutinize this, we used the mGRASP imaging technique to visualize synaptic modifications in a pathway formed between neurons of the posterior ventral segment of the medial amygdala and ventrolateral segment of the ventromedial hypothalamus (MeApv-VmHvl), areas we previously showed to be involved in stress-induced excessive aggression.

A single dose of ketamine enhances early life stress-induced aggression with no effect on fear memory, anxiety-like behavior, or depression-like behavior in mice.

Ketamine is a dissociative anesthetic that has been shown to have antidepressant effects in humans and has been proposed as a potential treatment for mood disorders such as posttraumatic stress disorder and aggression. However, previous studies from our lab and others have demonstrated that ketamine's effects are highly context- and dose-dependent. In a recent study, we found that 10 mg/kg ketamine could exacerbate the effects of early life stress on excessive aggression in mice.

Non-angry aggressive arousal and angriffsberietschaft: A narrative review of the phenomenology and physiology of proactive/offensive aggression motivation and escalation in people and other animals.

Human aggression typologies largely correspond with those for other animals. While there may be no non-human equivalent of angry reactive aggression, we propose that human proactive aggression is similar to offense in other animals' dominance contests for territory or social status. Like predation/hunting, but unlike defense, offense and proactive aggression are positively reinforcing, involving dopamine release in accumbens.

Promises and Pitfalls of NMDA Receptor Antagonists in Treating Violent Aggression.

Treatment options for chronically aggressive individuals remain limited despite recent medical advances. Traditional pharmacological agents used to treat aggression, such as atypical antipsychotics, have limited efficacy and are often replete with dangerous side effects. The non-competitive NMDAR antagonists ketamine and memantine are promising alternatives, but their effects appear to be highly dependent on dosage, context, and personal experience.

Opposing effects of NMDA receptor antagonists on early life stress-induced aggression in mice.

Rates of childhood trauma are high amongst violent offenders who frequently recidivate. Few clinical options are available to treat excessive and recurring violent aggression associated with childhood trauma. Those that do exist are largely ineffective and often replete with side effects.

Anger management: Mechanisms of glutamate receptor-mediated synaptic plasticity underlying animal aggression.

Excessive and recurring violent aggression is a serious concern for society and a symptom of many psychiatric diseases. Substance abuse, attack experience, and social and traumatic stress increase vulnerability to developing this type of aggression. Glutamate receptors are an intriguing target for long-term treatment.

Potentiation of Divergent Medial Amygdala Pathways Drives Experience-Dependent Aggression Escalation.

Heightened aggression can be serious concerns for the individual and society at large and are symptoms of many psychiatric illnesses, such as post-traumatic stress disorder. The circuit and synaptic mechanisms underlying experience-induced aggression increase, however, are poorly understood. Here we find that prior attack experience leading to an increase in aggressive behavior, known as aggression priming, activates neurons within the posterior ventral segment of the medial amygdala (MeApv).

Effects of Menthol on Nicotine Pharmacokinetic, Pharmacology and Dependence in Mice.

Although menthol, a common flavoring additive to cigarettes, has been found to impact the addictive properties of nicotine cigarettes in smokers little is known about its pharmacological and molecular actions in the brain. Studies were undertaken to examine whether the systemic administration of menthol would modulate nicotine pharmacokinetics, acute pharmacological effects (antinociception and hypothermia) and withdrawal in male ICR mice. In addition, we examined changes in the brain levels of nicotinic receptors of rodents exposed to nicotine and menthol.

Identification and Characterization of a G Protein-binding Cluster in α7 Nicotinic Acetylcholine Receptors.

α7 nicotinic acetylcholine receptors (nAChRs) play an important role in synaptic transmission and inflammation. In response to ligands, this receptor channel opens to conduct cations into the cell but desensitizes rapidly. In recent studies we show that α7 nAChRs bind signaling proteins such as heterotrimeric GTP-binding proteins (G proteins).

Microtubule dynamics at the growth cone are mediated by α7 nicotinic receptor activation of a Gαq and IP3 receptor pathway.

The α7 nicotinic receptor (α7) plays an important role in neuronal growth and structural plasticity in the developing brain. We have recently characterized a G-protein-signaling pathway regulated by α7 that directs the growth of neurites in developing neural cells. Now we show that choline activation of α7 promotes a rise in intracellular calcium from local ER stores via Gαq signaling, leading to IP3 receptor (IP3R) activation at the growth cone of differentiating PC12 cells.

Chemical crosslinkers enhance detection of receptor interactomes.

Receptor function is dependent on interaction with various intracellular proteins that ensure the localization and signaling of the receptor. While a number of approaches have been optimized for the isolation, purification, and proteomic characterization of receptor-protein interaction networks (interactomes) in cells, the capture of receptor interactomes and their dynamic properties remains a challenge. In particular, the study of interactome components that bind to the receptor with low affinity or can rapidly dissociate from the macromolecular complex is difficult.

Axon targeting of the alpha 7 nicotinic receptor in developing hippocampal neurons by Gprin1 regulates growth.

Cholinergic signaling plays an important role in regulating the growth and regeneration of axons in the nervous system. The α7 nicotinic receptor (α7) can drive synaptic development and plasticity in the hippocampus. Here, we show that activation of α7 significantly reduces axon growth in hippocampal neurons by coupling to G protein-regulated inducer of neurite outgrowth 1 (Gprin1), which targets it to the growth cone.

Are nicotinic acetylcholine receptors coupled to G proteins?

It was, until recently, accepted that the two classes of acetylcholine (ACh) receptors are distinct in an important sense: muscarinic ACh receptors signal via heterotrimeric GTP binding proteins (G proteins), whereas nicotinic ACh receptors (nAChRs) open to allow flux of Na+, Ca2+, and K+ ions into the cell after activation. Here we present evidence of direct coupling between G proteins and nAChRs in neurons. Based on proteomic, biophysical, and functional evidence, we hypothesize that binding to G proteins modulates the activity and signaling of nAChRs in cells.

The α4 nicotinic receptor promotes CD4+ T-cell proliferation and a helper T-cell immune response.

Smoking is a common addiction and a leading cause of disease. Chronic nicotine exposure is known to activate nicotinic acetylcholine receptors (nAChRs) in immune cells. We demonstrate a novel role for α4 nAChRs in the effect of nicotine on T-cell proliferation and immunity.

Menthol inhibits 5-HT3 receptor-mediated currents.

The effects of alcohol monoterpene menthol, a major active ingredient of the peppermint plant, were tested on the function of human 5-hydroxytryptamine type 3 (5-HT3) receptors expressed in Xenopus laevis oocytes. 5-HT (1 μM)-evoked currents recorded by two-electrode voltage-clamp technique were reversibly inhibited by menthol in a concentration-dependent (IC50 = 163 μM) manner. The effects of menthol developed gradually, reaching a steady-state level within 10-15 minutes and did not involve G-proteins, since GTPγS activity remained unaltered and the effect of menthol was not sensitive to pertussis toxin pretreatment.

Menthol binding and inhibition of α7-nicotinic acetylcholine receptors.

Menthol is a common compound in pharmaceutical and commercial products and a popular additive to cigarettes. The molecular targets of menthol remain poorly defined. In this study we show an effect of menthol on the α7 subunit of the nicotinic acetylcholine (nACh) receptor function.

Capture of D2 dopamine receptor signaling complexes in striatal cells for mass spectrometry proteomic analysis.

In recent years advancements in proteomic techniques have contributed to the understanding of protein interaction networks (Interactomes) in various cell types. Today, high throughput proteomics promises to define virtually all of the components of a signaling and a regulatory network within cells for various molecules including membrane-spanning receptors. The D2 dopamine receptor (D2R) is a primary mediator of dopamine transmission in the brain.

An interaction between α7 nicotinic receptors and a G-protein pathway complex regulates neurite growth in neural cells.

The α7 acetylcholine nicotinic receptor (α7) is an important mediator of cholinergic transmission during brain development. Here we present an intracellular signaling mechanism for the α7 receptor. Proteomic analysis of immunoprecipitated α7 subunits reveals an interaction with a G protein pathway complex (GPC) comprising Gα(i/o), GAP-43 and G protein regulated inducer of neurite outgrowth 1 (Gprin1) in differentiating cells.

Dopamine receptor interacting proteins: targeting neuronal calcium sensor-1/D2 dopamine receptor interaction for antipsychotic drug development.

D2 dopamine receptors (D2Rs) represent an important class of receptors in the pharmacological development of novel therapeutic drugs for the treatment of schizophrenia. Recent research into D2R signaling suggests that receptor properties are dependent on interaction with a cohort of dopamine receptor interacting proteins (DRIPs) within a macromolecular structure termed the signalplex. One component of this signalplex is neuronal calcium sensor 1 (NCS-1) a protein found to regulate the phosphorylation, trafficking, and signaling profile of the D2R in neurons.