Biofunctionalized gelatin hydrogels support development and maturation of iPSC-derived cortical organoids.

Human neural organoid models have become an important tool for studying neurobiology. However, improving the representativeness of neural cell populations in such organoids remains a major effort. In this work, we compared Matrigel, a commercially available matrix, to a neural cadherin (N-cadherin) peptide-functionalized gelatin methacryloyl hydrogel (termed GelMA-Cad) for culturing cortical neural organoids.

A Cocaine-Activated Ensemble Exerts Increased Control Over Behavior While Decreasing in Size.

Background: Substance use disorder is characterized by long-lasting changes in reward-related brain regions, such as the nucleus accumbens. Previous work has shown that cocaine exposure induces plasticity in broad, genetically defined cell types in the nucleus accumbens; however, in response to a stimulus, only a small percentage of neurons are transcriptionally active-termed an ensemble. Here, we identify an Arc-expressing neuronal ensemble that has a unique trajectory of recruitment and causally controls drug self-administration after repeated, but not acute, cocaine exposure.

D1 and D2 medium spiny neurons in the nucleus accumbens core have distinct and valence-independent roles in learning.

At the core of value-based learning is the nucleus accumbens (NAc). D1- and D2-receptor-containing medium spiny neurons (MSNs) in the NAc core are hypothesized to have opposing valence-based roles in behavior. Using optical imaging and manipulation approaches in mice, we show that neither D1 nor D2 MSNs signal valence.

Endocannabinoid release at ventral hippocampal-amygdala synapses regulates stress-induced behavioral adaptation.

The endocannabinoid (eCB) system is a key modulator of glutamate release within limbic neurocircuitry and thus heavily modulates stress responsivity and adaptation. The ventral hippocampus (vHPC)-basolateral amygdala (BLA) circuit has been implicated in the expression of negative affective states following stress exposure and is modulated by retrograde eCB signaling. However, the mechanisms governing eCB release and the causal relationship between vHPC-BLA eCB signaling and stress-induced behavioral adaptations are not known.

Synaptic and cellular endocannabinoid signaling mechanisms regulate stress-induced plasticity of nucleus accumbens somatostatin neurons.

Interneuron populations within the nucleus accumbens (NAc) orchestrate excitatory-inhibitory balance, undergo experience-dependent plasticity, and gate-motivated behavior, all biobehavioral processes heavily modulated by endogenous cannabinoid (eCB) signaling. While eCBs are well known to regulate synaptic plasticity onto NAc medium spiny neurons and modulate NAc function at the behavioral level, how eCBs regulate NAc interneuron function is less well understood. Here, we show that eCB signaling differentially regulates glutamatergic and feedforward GABAergic transmission onto NAc somatostatin-expressing interneurons (NAc) in an input-specific manner, while simultaneously increasing postsynaptic excitability of NAc neurons, ultimately biasing toward vHPC (ventral hippocampal), and away from BLA (basolateral amygdalalar), activation of NAc neurons.

SNAP25 differentially contributes to G-coupled receptor function at glutamatergic synapses in the nucleus accumbens.

The nucleus accumbens (NAc) guides reward-related motivated behavior implicated in pathological behavioral states, including addiction and depression. These behaviors depend on the precise neuromodulatory actions of G-coupled G-protein-coupled receptors (GPCRs) at glutamatergic synapses onto medium spiny projection neurons (MSNs). Previous work has shown that discrete classes of G-coupled GPCR mobilize Gβγ to inhibit vesicular neurotransmitter release via t-SNARE protein, SNAP25.

Cannabidiol Differentially Modulates Synaptic Release and Cellular Excitability in Amygdala Subnuclei.

Cannabidiol (CBD) is a non-psychoactive constituent of the plant that has purported effectiveness in treating an array of stress-related neuropsychiatric disorders. The amygdala is a subcortical brain structure that regulates emotional behavior, and its dysfunction has been linked to numerous disorders including anxiety and posttraumatic stress disorder. Despite this, the direct effects of CBD on synaptic and cellular function in the amygdala are not known.

Opposing retrograde and astrocyte-dependent endocannabinoid signaling mechanisms regulate lateral habenula synaptic transmission.

The lateral habenula (LHb) encodes aversive states, and its dysregulation is implicated in neuropsychiatric disorders, including depression. The endocannabinoid (eCB) system is a neuromodulatory signaling system that broadly serves to counteract the adverse effects of stress; however, CB receptor signaling within the LHb can paradoxically promote anxiogenic- and depressive-like effects. Current reports of synaptic actions of eCBs in the LHb are conflicting and lack systematic investigation of eCB regulation of excitatory and inhibitory transmission.

Photoperiod Impacts Nucleus Accumbens Dopamine Dynamics.

Circadian photoperiod, or day length, changes with the seasons and influences behavior to allow animals to adapt to their environment. Photoperiod is also associated with seasonal rhythms of affective state, as evidenced by seasonality of several neuropsychiatric disorders. Interestingly, seasonality tends to be more prevalent in women for affective disorders such as major depressive disorder and bipolar disorder (BD).

Ventral hippocampal diacylglycerol lipase-alpha deletion decreases avoidance behaviors and alters excitation-inhibition balance.

The endogenous cannabinoid, 2-arachidonoylglycerol (2-AG), plays a key role in the regulation of anxiety- and stress-related behavioral phenotypes and may represent a novel target for the treatment of anxiety disorders. However, recent studies have suggested a more complex role for 2-AG signaling in the regulation of stress responsivity, including increases in acute fear responses after 2-AG augmentation under some conditions. Thus, 2-AG signaling within distinct brain regions and circuits could regulate anxiety-like behavior and stress responsivity in opposing manners.

Neuropeptide Y modulates excitatory synaptic transmission and promotes social behavior in the mouse nucleus accumbens.

Social interactions define the human experience, but these integral behaviors are disrupted in many psychiatric disorders. Social behaviors have evolved over millennia, and neuromodulatory systems that promote social behavior in invertebrates are also present in mammalian brains. One such conserved neuromodulator, neuropeptide Y (NPY), acts through several receptors including the Y1r, Y2r, and Y5r.

Hunger dampens a nucleus accumbens circuit to drive persistent food seeking.

To find food efficiently, a hungry animal engages in goal-directed behaviors that rely on nucleus accumbens (NAc) circuits. Synaptic alterations within these circuits underlie shifts in behavior across motivational states. Here, we show that hunger dampens an NAc to lateral hypothalamus (LH) circuit to promote persistent food seeking.

FGF21 suppresses alcohol consumption through an amygdalo-striatal circuit.

Excessive alcohol consumption is a major health and social issue in our society. Pharmacologic administration of the endocrine hormone fibroblast growth factor 21 (FGF21) suppresses alcohol consumption through actions in the brain in rodents, and genome-wide association studies have identified single nucleotide polymorphisms in genes involved with FGF21 signaling as being associated with increased alcohol consumption in humans. However, the neural circuit(s) through which FGF21 signals to suppress alcohol consumption are unknown, as are its effects on alcohol consumption in higher organisms.

TAAR1 regulates drug-induced reinstatement of cocaine-seeking via negatively modulating CaMKIIα activity in the NAc.

Relapse remains a major challenge to the treatment of cocaine addiction. Recent studies suggested that the trace amine-associated receptor 1 (TAAR1) could be a promising target to treat cocaine addiction and relapse; however, the underlying mechanism remains unclear. Here, we aimed to investigate the neural mechanism underlying the role of TAAR1 in the drug priming-induced reinstatement of cocaine-seeking behavior in rats, an animal model of cocaine relapse.

Accumbal Histamine Signaling Engages Discrete Interneuron Microcircuits.

Background: Central histamine (HA) signaling modulates diverse cortical and subcortical circuits throughout the brain, including the nucleus accumbens (NAc). The NAc, a key striatal subregion directing reward-related behavior, expresses diverse HA receptor subtypes that elicit cellular and synaptic plasticity. However, the neuromodulatory capacity of HA within interneuron microcircuits in the NAc remains unknown.

Robust Expression of Functional NMDA Receptors in Human Induced Pluripotent Stem Cell-Derived Neuronal Cultures Using an Accelerated Protocol.

N-methyl-D-aspartate (NMDA) receptors are critical for higher-order nervous system function, but in previously published protocols to convert human induced pluripotent stem cells (iPSCs) to mature neurons, functional NMDA receptors (NMDARs) are often either not reported or take an extended time to develop. Here, we describe a protocol to convert human iPSC-derived neural progenitor cells (NPCs) to mature neurons in only 37 days. We demonstrate that the mature neurons express functional NMDARs exhibiting ligand-activated calcium flux, and we document the presence of NMDAR-mediated electrically evoked postsynaptic current.

Cocaine restricts nucleus accumbens feedforward drive through a monoamine-independent mechanism.

Parvalbumin-expressing fast-spiking interneurons (PV-INs) within feedforward microcircuits in the nucleus accumbens (NAc) coordinate goal-directed motivational behavior. Feedforward inhibition of medium spiny projection neurons (MSNs) is initiated by glutamatergic input from corticolimbic brain structures. While corticolimbic synapses onto MSNs are targeted by the psychostimulant, cocaine, it remains unknown whether cocaine also exerts acute neuromodulatory actions at collateralizing synapses onto PV-INs.

Kappa opioid receptor modulation of excitatory drive onto nucleus accumbens fast-spiking interneurons.

The dynorphin/kappa opioid receptor (KOR) system within the nucleus accumbens (NAc) contributes to affective states. Parvalbumin fast-spiking interneurons (PV-FSIs), a key component of feedforward inhibition, participate in integration of excitatory inputs to the NAc by robustly inhibiting select populations of medium spiny output neurons, therefore greatly influencing NAc dependent behavior. How the dynorphin/KOR system regulates feedforward inhibition in the NAc remains unknown.

Patch-clamp and multi-electrode array electrophysiological analysis in acute mouse brain slices.

Patch-clamp and multi-electrode array electrophysiology techniques are used to measure dynamic functional properties of neurons. Whole-cell and cell-attached patch-clamp recordings in brain slices can be performed in voltage-clamp and current-clamp configuration to reveal cell-type-specific synaptic and cellular parameters governing neurotransmission. Multi-electrode array electrophysiology can provide spike activity recordings from multiple neurons, enabling larger sample sizes, and long-term recordings.

Noradrenergic Signaling Disengages Feedforward Transmission in the Nucleus Accumbens Shell.

The nucleus accumbens shell (NAcSh) receives extensive monoaminergic input from multiple midbrain structures. However, little is known how norepinephrine (NE) modulates NAc circuit dynamics. Using a dynamic electrophysiological approach with optogenetics, pharmacology, and drugs acutely restricted by tethering (DART), we explored microcircuit-specific neuromodulatory mechanisms recruited by NE signaling in the NAcSh of parvalbumin (PV)-specific reporter mice.

Hunger-driven adaptive prioritization of behavior.

In order to survive, an animal must adapt its behavioral priorities to accommodate changing internal and external conditions. Hunger, a universally recognized interoceptive signal, promotes food intake though increasingly well-understood neural circuits. Less understood, is how hunger is integrated into the neural computations that guide nonfeeding behaviors.

Cannabinoid type 1 receptors in A2a neurons contribute to cocaine-environment association.

Rationale: Cannabinoid type 1 receptors (CB1Rs) are widely expressed within the brain's reward circuits and are implicated in regulating drug induced behavioral adaptations. Understanding how CB1R signaling in discrete circuits and cell types contributes to drug-related behavior provides further insight into the pathology of substance use disorders.

Objective And Methods: We sought to determine how cell type-specific expression of CB1Rs within striatal circuits contributes to cocaine-induced behavioral plasticity, hypothesizing that CB1R function in distinct striatal neuron populations would differentially impact behavioral outcomes.

Activation of proline biosynthesis is critical to maintain glutamate homeostasis during acute methamphetamine exposure.

Methamphetamine (METH) is a highly addictive psychostimulant that causes long-lasting effects in the brain and increases the risk of developing neurodegenerative diseases. The cellular and molecular effects of METH in the brain are functionally linked to alterations in glutamate levels. Despite the well-documented effects of METH on glutamate neurotransmission, the underlying mechanism by which METH alters glutamate levels is not clearly understood.

Rhythms, Reward, and Blues: Consequences of Circadian Photoperiod on Affective and Reward Circuit Function.

Circadian disruptions, along with altered affective and reward states, are commonly associated with psychiatric disorders. In addition to genetics, the enduring influence of environmental factors in programming neural networks is of increased interest in assessing the underpinnings of mental health. The duration of daylight or photoperiod is known to impact both the serotonin and dopamine systems, which are implicated in mood and reward-based disorders.