Finding the link between behaviors and their regulatory molecular pathways is a major obstacle in treating neuropsychiatric disorders. The immediate early gene (IEG) EGR1 is implicated in the etiology of neuropsychiatric disorders, and is linked to gene pathways associated with social behavior. Despite extensive knowledge of EGR1 gene regulation at the molecular level, it remains unclear how EGR1 deficits might affect the social component of these disorders. Here, we examined the social behavior of zebrafish with a mutation in the homologous gene egr1 . Mutant fish exhibited reduced social approach and orienting, whereas other sensorimotor behaviors were unaffected. On a molecular level, expression of the dopaminergic biosynthetic enzyme, tyrosine hydroxylase (TH), was strongly decreased in TH-positive neurons of the anterior parvocellular preoptic nucleus. These neurons are connected with basal forebrain (BF) neurons associated with social behavior. Chemogenetic ablation of around 30% of TH-positive neuro...

In the olfactory bulb, mitral cells (MCs) display a spontaneous firing that is characterized by bursts of action potentials (APs) intermixed with silent periods. Intraburst firing frequency and duration are heterogeneous among MCs and increase with membrane depolarization. By using patch-clamp recording on rat slices, we dissected out the intrinsic properties responsible for this bursting activity. We showed that the threshold of AP generation dynamically changes as a function of the preceding trajectory of the membrane potential. In fact, the AP threshold became more negative when the membrane was hyperpolarized and had a recovery rate inversely proportional to the membrane repolarization rate. Such variations appeared to be produced by changes in the inactivation state of voltage-dependent Na+ channels. Thus, AP initiation was favored by hyperpolarizing events, such as negative membrane oscillations or inhibitory synaptic input. After the first AP, the following fast afterhyperpolarization (AHP) brought ...

Motor cortical neurons exhibit persistent selective activities (selectivity) during motor planning. Experimental perturbation of selectivity results in the failure of short-term memory retention and consequent behavioral biases, demonstrating selectivity as a neural characteristic of encoding previous sensory input or future action. However, even without experimental manipulation, animals occasionally fail to maintain short-term memory leading to erroneous choice. Here, we investigated neural substrates that lead to the incorrect formation of selectivity during short-term memory. We analyzed neuronal activities in anterior lateral motor cortex (ALM) of mice, a region known to be engaged in motor planning while mice performed the tactile delayed-response task. We found that highly selective neurons lost their selectivity while originally nonselective neurons showed selectivity during the error trials where mice licked toward incorrect direction. We assumed that those alternations would reflect changes in in...

Dynamic functional connectivity within brain circuits requires coordination of intercellular signaling and intracellular signal transduction. Critical roles for cAMP-dependent protein kinase A (PKA) signaling are well established in the Drosophila mushroom body (MB) learning and memory circuitry, but local PKA activity within this well-mapped neuronal network is uncharacterized. Here, we use an in vivo PKA activity sensor (PKA-SPARK) to test spatiotemporal regulatory requirements in the MB axon lobes. We find immature animals have little detectable PKA activity, whereas postcritical period adults show high field-selective activation primarily in just 3/16 defined output regions. In addition to the age-dependent PKA activity in distinct α’/β’ lobe nodes, females show sex-dependent elevation compared with males in these same restricted regions. Loss of neural cell body Fragile X mental retardation protein (FMRP) and Rugose [human Neurobeachin (NBEA)] suppresses localized PKA activity, whereas overexpression ...

Working memory, a core function underlying many higher-level cognitive processes, requires cooperation of multiple brain regions. White matter refers to myelinated axons, which are critical to interregional brain communication. Past studies on the association between white-matter integrity and working memory have yielded mixed findings. Using voxelwise tract-based spatial statistics analysis, we investigated this relationship in a sample of 328 healthy adults from 25 to 80 years of age. Given the important role of dopamine (DA) in working-memory functioning and white matter, we also analyzed the effects of dopamine-related genes on them. There were associations between white-matter integrity and working memory in multiple tracts, indicating that working-memory functioning relies on global connections between different brain areas across the adult life span. Moreover, a mediation analysis suggested that white-matter integrity contributes to age-related differences in working memory. Finally, there was an ef...

The marble burying test is a commonly used paradigm to describe phenotypes in mouse models of neurodevelopmental and psychiatric disorders. The current methodological approach relies predominantly on reporting the number of buried marbles at the end of the test. By measuring the proxy of the behavior (buried marbles), many important characteristics regarding the temporal aspect of this assay are lost. Here, we introduce a novel, automated method to quantify mouse behavior during the marble burying test with the focus on the burying bouts and movement dynamics. Using open-source software packages, we trained a supervised machine learning algorithm (the “classifier”) to distinguish burying behavior in freely moving mice. In order to confirm the classifier’s accuracy and characterize burying events in high detail, we performed the marble burying test in three mouse models: Ube3am-/p+ [Angelman syndrome (AS) model], Shank2 −/− (autism model), and Sapap3 −/− [obsessive-compulsive disorder (OCD) model] mice. The...

Survival for vertebrate animals is dependent on the ability to successfully find food, locate a mate, and avoid predation. Each of these behaviors requires motor control, which is set by a combination of kinematic properties. For example, the frequency and amplitude of motor output combine in a multiplicative manner to determine features of locomotion such as distance traveled, speed, force (thrust), and vigor. Although there is a good understanding of how different populations of excitatory spinal interneurons establish locomotor frequency, there is a less thorough mechanistic understanding for how locomotor amplitude is established. Recent evidence indicates that locomotor amplitude is regulated in part by a subset of functionally and morphologically distinct V2a excitatory spinal interneurons (Type II, nonbursting) in larval and adult zebrafish. Here, we provide direct evidence that most V3 interneurons (V3-INs), which are a developmentally and genetically defined population of ventromedial glutamatergi...

Learning associations between cues and rewards require the mesolimbic dopamine system. The dopamine response to cues signals differences in reward value in well trained animals. However, these value-related dopamine responses are absent during early training sessions when cues signal differences in the reward rate. These findings suggest cue-evoked dopamine release conveys differences between outcomes only after extensive training, though it is unclear whether this is unique to when cues signal differences in reward rate, or whether this is also evident when cues signal differences in other value-related parameters such as reward size. To address this, we used a Pavlovian conditioning task in which one audio cue was associated with a small reward (one pellet) and another audio cue was associated with a large reward (three pellets). We performed fast-scan cyclic voltammetry to record changes in dopamine release in the nucleus accumbens of male and female rats throughout learning. While female rats exhibited...

Responsible science has three components: doing science, the validity of the discoveries themselves, and the consequences of these discoveries. These three components are nondissociable, because science does not exist by and for itself: it exists within a societal context. Society and Science always interact with each other. Doing science has direct societal consequences, which can be positive, including novel therapeutic solutions and general advancement of knowledge, and negative, including using planet resources, producing waste, and contributing to global warming (with travel, for example). I shall not develop the latter components here; I shall develop the validity of the discoveries and their consequences in the present context of the immediacy of information and “selfie” science. An idealistic and naive depiction of a scientist is someone concerned only with the internal content of their scientific work and not with their external repercussions. A scientist is but one part of the complex organism t...

The neural basis of attention is thought to involve the allocation of limited neural resources. However, the quantitative validation of this hypothesis remains challenging. Here, we provide quantitative evidence that the nonuniform allocation of neural resources across the whole cerebral gray matter reflects the broad-task process of sustained attention. We propose a neural measure for the nonuniformity of whole-cerebral allocation using functional magnetic resonance imaging. We found that this measure was significantly correlated with conventional indicators of attention level, such as task difficulty and pupil dilation. We further found that the broad-task neural correlates of the measure belong to frontoparietal and dorsal attention networks. Finally, we found that patients with attention-deficit/hyperactivity disorder showed abnormal decreases in the level of the proposed measure, reflecting the executive dysfunction. This study proposes a neuromarker suggesting that the nonuniform allocation of neural...