The neurotransmitter dopamine is implicated in diverse functions, including reward processing, reinforcement learning, and cognitive control. The tendency to discount future rewards over time has long been discussed in the context of potential dopaminergic modulation. Here we examined the effect of a single dose of the D2 receptor antagonist haloperidol (2 mg) on temporal discounting in healthy female and male human participants. Our approach extends previous pharmacological studies in two ways. First, we applied combined temporal discounting drift diffusion models to examine choice dynamics. Second, we examined dopaminergic modulation of reward magnitude effects on temporal discounting. Hierarchical Bayesian parameter estimation revealed that the data were best accounted for by a temporal discounting drift diffusion model with nonlinear trialwise drift rate scaling. This model showed good parameter recovery, and posterior predictive checks revealed that it accurately reproduced the relationship between de...

SYNGAP1 is a major genetic risk factor for global developmental delay, autism spectrum disorder, and epileptic encephalopathy. De novo loss-of-function variants in this gene cause a neurodevelopmental disorder defined by cognitive impairment, social-communication disorder, and early-onset seizures. Cell biological studies in mouse and rat neurons have shown that Syngap1 regulates developing excitatory synapse structure and function, with loss-of-function variants driving formation of larger dendritic spines and stronger glutamatergic transmission. However, studies to date have been limited to mouse and rat neurons. Therefore, it remains unknown how SYNGAP1 loss of function impacts the development and function of human neurons. To address this, we used CRISPR/Cas9 technology to ablate SYNGAP1 protein expression in neurons derived from a commercially available induced pluripotent stem cell line (hiPSC) obtained from a human female donor. Reducing SynGAP protein expression in developing hiPSC-derived neurons ...

Caitlin Baumer-Harrison, Martin A. Raymond, Thomas A. Myers, Kolbe M. Sussman, Spencer T. Rynberg, et al. (see pages [7795–7810][1]) Taste perception is transduced by receptors and channels expressed in different types of taste bud cells. Sweet, umami, and bitter tastes are transduced by G-

Neurons are noisy. Neuronal activity varies in response to repetitions of the same stimulus. Neuronal noise is ubiquitous in the brain and is often correlated among neighboring neurons, which means that stimulus-independent fluctuations in neuronal activity can affect entire populations of cells ([

The frontal cortex and temporal lobes together regulate complex learning and memory capabilities. Here, we collected resting-state functional and diffusion-weighted MRI data before and after male rhesus macaque monkeys received extensive training to learn novel visuospatial discriminations (reward-guided learning). We found functional connectivity changes in orbitofrontal, ventromedial prefrontal, inferotemporal, entorhinal, retrosplenial, and anterior cingulate cortices, the subicular complex, and the dorsal, medial thalamus. These corticocortical and thalamocortical changes in functional connectivity were accompanied by related white matter structural alterations in the uncinate fasciculus, fornix, and ventral prefrontal tract: tracts that connect (sub)cortical networks and are implicated in learning and memory processes in monkeys and humans. After the well-trained monkeys received fornix transection, they were impaired in learning new visuospatial discriminations. In addition, the functional connectivi...

As one of the thalamic midline nuclei, the thalamic paraventricular nucleus (PVT) is considered to be an important signal integration site for many descending and ascending pathways that modulate a variety of behaviors, including feeding, emotions, and drug-seeking. A recent study has demonstrated that the PVT is implicated in the acute visceral pain response, but it is unclear whether the PVT plays a critical role in the central processing of chronic pain. Here, we report that the neurons in the posterior portion of the PVT (pPVT) and their downstream pathway are involved in descending nociceptive facilitation regarding the development of neuropathic pain conditions in male rats. Lesions or inhibition of pPVT neurons alleviated mechanical allodynia induced by spared nerve injury (SNI). The excitability of pPVT-central amygdala (CeA) projection neurons was significantly increased in SNI rats. Importantly, selective optogenetic activation of the pPVT-CeA pathway induced obvious mechanical hypersensitivity i...

Mammalian taste buds are comprised of specialized neuroepithelial cells that act as sensors for molecules that provide nutrition (e.g., carbohydrates, amino acids, and salts) and those that are potentially harmful (e.g., certain plant compounds and strong acids). Type II and III taste bud cells (TBCs) detect molecules described by humans as “sweet,” “bitter,” “umami,” and “sour.” TBCs that detect metallic ions, described by humans as “salty,” are undefined. Historically, type I glial-like TBCs have been thought to play a supportive role in the taste bud, but little research has been done to explore their role in taste transduction. Some evidence implies that type I cells may detect sodium (Na+) via an amiloride-sensitive mechanism, suggesting they play a role in Na+ taste transduction. We used an optogenetic approach to study type I TBCs by driving the expression of the light-sensitive channelrhodopsin-2 (ChR2) in type I GAD65+ TBCs of male and female mice. Optogenetic stimulation of GAD65+ TBCs increased ...

When extreme, anxiety—a state of distress and arousal prototypically evoked by uncertain danger—can be debilitating. Uncertain anticipation is a shared feature of situations that elicit signs and symptoms of anxiety across psychiatric disorders, species, and assays. Despite the profound significance of anxiety for human health and wellbeing, the neurobiology of uncertain-threat anticipation remains unsettled. Leveraging a paradigm adapted from animal research and optimized for fMRI signal decomposition, we examined the neural circuits engaged during the anticipation of temporally uncertain and certain threat in 99 men and women. Results revealed that the neural systems recruited by uncertain and certain threat anticipation are anatomically colocalized in frontocortical regions, extended amygdala, and periaqueductal gray. Comparison of the threat conditions demonstrated that this circuitry can be fractionated, with frontocortical regions showing relatively stronger engagement during the anticipation of unce...

Larval zebrafish possess a number of molecular and genetic advantages for rigorous biological analyses of learning and memory. These advantages have motivated the search for novel forms of memory in these animals that can be exploited for understanding the cellular and molecular bases of vertebrate memory formation and consolidation. Here we report a new form of behavioral sensitization in zebrafish larvae that is elicited by an aversive chemical stimulus (allyl isothiocyanate) and that persists for ≥ 30 min. This form of sensitization is expressed as enhanced locomotion and thigmotaxis, as well as elevated heart rate. To characterize the neural basis of this nonassociative memory, we used transgenic zebrafish expressing the fluorescent calcium indicator GCaMP6 (Chen et al., 2013); due to the transparency of larval zebrafish, we could optically monitor neural activity in the brain of intact transgenic zebrafish before and after the induction of sensitization. We found a distinct brain area, previously link...