Optogenetics and behavior

MDMA (3,4-methylenedioxymethamphetamine) is a psychoactive drug with powerful prosocial effects. While MDMA is sometimes termed an "empathogen," empirical studies have struggled to clearly demonstrate these effects or pinpoint underlying mechanisms. Here, we paired the social transfer of pain and analgesia-behavioral tests modeling empathy in mice-with region-specific neuropharmacology, optogenetics, and transgenic manipulations to explore MDMA's action as an empathogen. We report that MDMA, given intraperitoneally or infused directly into the nucleus accumbens (NAc), robustly enhances the social transfer of pain and analgesia...

Obesity is a major global health epidemic that has adverse effects on both the people affected as well as the cost to society. Several anti-obesity drugs that target GLP-1 receptors have recently come to the market. Here, we describe the effects of tesofensine, a novel anti-obesity drug that acts as a triple monoamine neurotransmitter reuptake inhibitor. Using various techniques, we investigated its effects on weight loss and underlying neuronal mechanisms in mice and rats. These include behavioral tasks, DeepLabCut videotaped analysis, electrophysiological ensemble recordings, optogenetic activation, and chemogenetic silencing of GABAergic neurons in the Lateral Hypothalamus (LH)...

Obstructive sleep apnea (OSA) is a prevalent sleep-related breathing disorder that results in multiple bouts of intermittent hypoxia. OSA has many neurological and systemic comorbidities, including dysphagia, or disordered swallow, and discoordination with breathing. However, the mechanism in which chronic intermittent hypoxia (CIH) causes dysphagia is unknown. Recently, we showed the postinspiratory complex (PiCo) acts as an interface between the swallow pattern generator (SPG) and the inspiratory rhythm generator, the preBötzinger complex, to regulate proper swallow-breathing coordination (Huff et al...

Dysregulation of the central amygdala is thought to underlie aberrant choice in alcohol use disorder, but the role of central amygdala neural activity during reward choice and consumption is unclear. We recorded central amygdala neurons in male rats as they consumed alcohol or sucrose. We observed activity changes at the time of reward approach, as well as lick-entrained activity during ongoing consumption of both rewards. In choice scenarios where rats could drink sucrose, alcohol, or quinine-adulterated alcohol with or without central amygdala optogenetic stimulation, rats drank more of stimulation-paired options when the two bottles contained identical options...

Neurons in primary visual cortex integrate sensory input with signals reflecting the animal's internal state to support flexible behavior. Internal variables, such as expectation, attention, or current goals, are imposed in a top-down manner via extensive feedback projections from higher-order areas. We optogenetically activated a high-order visual area, area 21a, in the lightly anesthetized cat (OptoTD), while recording from neuronal populations in V1. OptoTD induced strong, up to several fold, changes in gamma-band synchronization together with much smaller changes in firing rate, and the two effects showed no correlation...

Assessing and responding to threats is vital in everyday life. Unfortunately, many mental illnesses involve impaired risk assessment, affecting patients, families, and society. The brain processes behind these behaviors are not well understood. We developed a transgenic mouse model (disrupted-in-schizophrenia 1 [DISC1]-N) with a disrupted avoidance response in risky settings. Our study utilized single-nucleus RNA sequencing and path-clamp coupling with real-time RT-PCR to uncover a previously undescribed group of glutamatergic neurons in the basolateral amygdala (BLA) marked by Wolfram syndrome 1 (WFS1) expression, whose activity is modulated by adjacent astrocytes...

The primary visual cortex (V1) and the superior colliculus (SC) both occupy stations early in the processing of visual information. They have long been thought to perform distinct functions, with the V1 supporting the perception of visual features and the SC regulating orienting to visual inputs. However, growing evidence suggests that the SC supports the perception of many of the same visual features traditionally associated with the V1. To distinguish V1 and SC contributions to visual processing, it is critical to determine whether both areas causally contribute to the detection of specific visual stimuli...

Neurons in the inferotemporal (IT) cortex respond selectively to complex visual features, implying their role in object perception. However, perception is subjective and cannot be read out from neural responses; thus, bridging the causal gap between neural activity and perception demands independent characterization of perception. Historically, though, the complexity of the perceptual alterations induced by artificial stimulation of IT cortex has rendered them impossible to quantify. To address this old problem, we tasked male macaque monkeys to detect and report optical impulses delivered to their IT cortex...

Perioperative neurocognitive disorder (PND) is a common complication in surgical patients. While many interventions to prevent PND have been studied, the availability of treatment methods is limited. Thus, it is crucial to delve into the mechanisms of PND, pinpoint therapeutic targets, and develop effective treatment approaches. In this study, reduced dorsal tenia tecta (DTT) neuronal activity was found to be associated with tibial fracture surgery-induced PND, indicating that a neuronal excitation-inhibition (E-I) imbalance could contribute to PND...

Organisms surveil and respond to their environment using behaviors entrained by metabolic cues that reflect food availability. Mitochondria act as metabolic hubs and at the center of mitochondrial energy production is the protonmotive force (PMF), an electrochemical gradient generated by metabolite consumption. The PMF serves as a central integrator of mitochondrial status, but its role in governing metabolic signaling is poorly understood. We used optogenetics to dissipate the PMF in Caenorhabditis elegans tissues to test its role in food-related behaviors...

Behavioral plasticity is subjected to various sensory stimuli, experiences, and physiological states, representing the temporal and spatial patterns of neural circuit dynamics. Elucidation of how genes and neural circuits in our brain actuate behavioral plasticity requires functional imaging during behavioral assays to manifest temporal and spatial neural regulation in behaviors. The exploration of the nervous systems of Caenorhabditis elegans has catalyzed substantial scientific advancements in elucidating the mechanistic link between circuit dynamics and behavioral plasticity...

INTRODUCTION: Subjective tinnitus, the perception of sound without an external acoustic source, is often subsequent to noise-induced hearing loss or ototoxic medications. The condition is believed to result from neuroplastic alterations in the auditory centers, characterized by heightened spontaneous neural activities and increased synchrony due to an imbalance between excitation and inhibition. However, the role of the thalamic reticular nucleus (TRN), a structure composed exclusively of GABAergic neurons involved in thalamocortical oscillations, in the pathogenesis of tinnitus remains largely unexplored...

Biomolecular condensates, often assembled through phase transition mechanisms, play key roles in organizing diverse cellular activities. The material properties of condensates, ranging from liquid droplets to solid-like glasses or gels, are key features impacting the way resident components associate with one another. However, it remains unclear whether and how different material properties would influence specific cellular functions of condensates. Here, we combine optogenetic control of phase separation with single-molecule mRNA imaging to study relations between phase behaviors and functional performance of condensates...

The transition of bacteria from an individualistic to a biofilm lifestyle profoundly alters their biology. During biofilm development, the bacterial cell-cell adhesions are a major determinant of initial microcolonies, which serve as kernels for the subsequent microscopic and mesoscopic structure of the biofilm, and determine the resulting functionality. In this study, the significance of bacterial cell-cell adhesion dynamics on bacterial aggregation and biofilm maturation is elucidated. Using photoswitchable adhesins between bacteria, modifying the dynamics of bacterial cell-cell adhesions with periodic dark-light cycles is systematic...

The dorsal hippocampus (dHPC) is a key brain region for the expression of spatial memories, such as navigating towards a learned reward location. The nucleus accumbens (NAc) is a prominent projection target of dHPC and implicated in value-based action selection. Yet, the contents of the dHPC→NAc information stream and their acute role in behavior remain largely unknown. Here, we found that optogenetic stimulation of the dHPC→NAc pathway while mice navigated towards a learned reward location was both necessary and sufficient for spatial memory-related appetitive behaviors...

Temporally coordinated neural activity is central to nervous system function and purposeful behavior. Still, there is a paucity of evidence demonstrating how this coordinated activity within cortical and subcortical regions governs behavior. We investigated this between the primary motor (M1) and contralateral cerebellar cortex as rats learned a neuroprosthetic/brain-machine interface (BMI) task. In neuroprosthetic task, actuator movements are causally linked to M1 "direct" neurons that drive the decoder for successful task execution...

Preclinical research has demonstrated the efficacy of CB1 receptor (CB1R) antagonists in reducing drug-taking behavior. However, clinical trials with rimonabant, a CB1R antagonist with inverse agonist profile, failed due to severe adverse effects, such as depression and suicidality. As a result, efforts have shifted towards developing novel neutral CB1R antagonists without an inverse agonist profile for treating substance use disorders. Here, we assessed AM6527, a CB1R neutral antagonist, in addiction animal models...

The behavior of stem cells is regulated by mechanical cues in their niche that continuously vary due to extracellular matrix (ECM) remodeling, pulsated mechanical stress exerted by blood flow, and/or cell migration. However, it is still unclear how dynamics of mechanical cues influence stem cell lineage commitment, especially in a 3D microenvironment where mechanosensing differs from that in a 2D microenvironment. In the present study, we investigated how temporally varying mechanical signaling regulates expression of the early growth response 1 gene (Egr1), which we recently discovered to be a 3D matrix-specific mediator of mechanosensitive neural stem cell (NSC) lineage commitment...

Layer 5 neurons of the neocortex receive their principal inputs from layer 2/3 neurons. We seek to identify the nature and extent of the plasticity of these projections with motor learning. Using optogenetic and viral intersectional tools to selectively stimulate distinct neuronal subsets in rat primary motor cortex, we simultaneously record from pairs of corticospinal neurons associated with distinct features of motor output control: distal forelimb vs. proximal forelimb. Activation of Channelrhodopsin2-expressing layer 2/3 afferents onto layer 5 in untrained animals produces greater monosynaptic excitation of neurons controlling the proximal forelimb...

Two subtypes of striatal spiny projection neurons, iSPNs and dSPNs, whose axons form the "indirect" and "direct" pathways of the basal ganglia respectively, both make synaptic connections in the external globus pallidus (GPe), but are usually found to have different effects on behavior. Activation of the terminal fields of iSPNs or dSPNs generated compound currents in almost all GPe neurons. To determine whether iSPNs and dSPNs have the same or different effects on pallidal neurons, we studied the unitary synaptic currents generated in GPe neurons by action potentials in single striatal neurons...