Inhibition of striatal indirect pathway during second postnatal week leads to long-lasting deficits in motivated behavior.

Schizophrenia is a neuropsychiatric disorder with postulated neurodevelopmental etiology. Genetic and imaging studies have shown enhanced dopamine and D2 receptor occupancy in the striatum of patients with schizophrenia. However, whether alterations in postnatal striatal dopamine can lead to long-lasting changes in brain function and behavior is still unclear.

Adolescent Thalamoprefrontal Inhibition Leads to Changes in Intrinsic Prefrontal Network Connectivity.

Adolescent inhibition of thalamocortical projections from postnatal days P20 to 50 leads to long-lasting deficits in prefrontal cortex function and cognition in the adult mouse. While this suggests a role of thalamic activity in prefrontal cortex maturation, it is unclear how inhibition of these projections affects prefrontal circuitry during adolescence. Here, we used chemogenetic tools to inhibit thalamoprefrontal projections in male/female mice from P20 to P35 and measured synaptic inputs to prefrontal pyramidal neurons by layer (either II/III or V/VI) and projection target (mediodorsal thalamus (MD), nucleus accumbens (NAc), or callosal prefrontal projections) 24 h later using slice physiology.

Adolescent Thalamocortical Inhibition Alters Prefrontal Excitation-Inhibition Balance.

Adolescent inhibition of thalamo-cortical projections from postnatal day P20-50 leads to long lasting deficits in prefrontal cortex function and cognition in the adult mouse. While this suggests a role of thalamic activity in prefrontal cortex maturation, it is unclear how inhibition of these projections affects prefrontal circuit connectivity during adolescence. Here, we used chemogenetic tools to inhibit thalamo-prefrontal projections in the mouse from P20-35 and measured synaptic inputs to prefrontal pyramidal neurons by layer (either II/III or V/VI) and projection target twenty-four hours later using slice physiology.

A non-canonical striatopallidal Go pathway that supports motor control.

In the classical model of the basal ganglia, direct pathway striatal projection neurons (dSPNs) send projections to the substantia nigra (SNr) and entopeduncular nucleus to regulate motor function. Recent studies have re-established that dSPNs also possess axon collaterals within the globus pallidus (GPe) (bridging collaterals), yet the significance of these collaterals for behavior is unknown. Here we use in vivo optical and chemogenetic tools combined with deep learning approaches in mice to dissect the roles of dSPN GPe collaterals in motor function.

Dopaminergic D2 receptor modulation of striatal cholinergic interneurons contributes to sequence learning.

Learning action sequences is necessary for normal daily activities. Medium spiny neurons (MSNs) in the dorsal striatum (dStr) encode action sequences through changes in firing at the start and/or stop of action sequences or sustained changes in firing throughout the sequence. Acetylcholine (ACh), released from cholinergic interneurons (ChIs), regulates striatal function by modulating MSN and interneuron excitability, dopamine and glutamate release, and synaptic plasticity.

Locus of control: How the brain gives up when failure is taken for granted.

After repeatedly failing to get out of a stressful, uncontrollable environment, mice switch from escape behavior to inactivity. In this issue of Neuron, Li et al. identify a circuit involving noradrenergic projections from the locus coeruleus to GABAergic projection neurons in the orbitofrontal cortex that participate in this adaptive behavior.

Mature parvalbumin interneuron function in prefrontal cortex requires activity during a postnatal sensitive period.

In their seminal findings, Hubel and Wiesel identified sensitive periods in which experience can exert lasting effects on adult visual cortical functioning and behavior via transient changes in neuronal activity during development. Whether comparable sensitive periods exist for non-sensory cortices, such as the prefrontal cortex, in which alterations in activity determine adult circuit function and behavior is still an active area of research. Here, using mice we demonstrate that inhibition of prefrontal parvalbumin (PV)-expressing interneurons during the juvenile and adolescent period, results in impairments in adult prefrontal circuit connectivity, in vivo network function, and behavioral flexibility that can be reversed by targeted activation of PV interneurons in adulthood.

Dopamine D2 receptors bidirectionally regulate striatal enkephalin expression: Implications for cocaine reward.

Low dopamine D2 receptor (D2R) availability in the striatum can predispose for cocaine abuse; though how low striatal D2Rs facilitate cocaine reward is unclear. Overexpression of D2Rs in striatal neurons or activation of D2Rs by acute cocaine suppresses striatal Penk mRNA. Conversely, low D2Rs in D2-striatal neurons increases striatal Penk mRNA and enkephalin peptide tone, an endogenous mu-opioid agonist.

Adolescent thalamic inhibition leads to long-lasting impairments in prefrontal cortex function.

Impaired cortical maturation is a postulated mechanism in the etiology of neurodevelopmental disorders, including schizophrenia. In the sensory cortex, activity relayed by the thalamus during a postnatal sensitive period is essential for proper cortical maturation. Whether thalamic activity also shapes prefrontal cortical maturation is unknown.

Thalamocortical Development: A Neurodevelopmental Framework for Schizophrenia.

Adolescence is a period of increased vulnerability for the development of psychiatric disorders, including schizophrenia. The prefrontal cortex (PFC) undergoes substantial maturation during this period, and PFC dysfunction is central to cognitive impairments in schizophrenia. As a result, impaired adolescent maturation of the PFC has been proposed as a mechanism in the etiology of the disorder and its cognitive symptoms.

Dopamine D2 receptors modulate the cholinergic pause and inhibitory learning.

Cholinergic interneurons (CINs) in the striatum respond to salient stimuli with a multiphasic response, including a pause, in neuronal activity. Slice-physiology experiments have shown the importance of dopamine D2 receptors (D2Rs) in regulating CIN pausing, yet the behavioral significance of the CIN pause and its regulation by dopamine in vivo is still unclear. Here, we show that D2R upregulation in CINs of the nucleus accumbens (NAc) lengthens the pause in CIN activity ex vivo and enlarges a stimulus-evoked decrease in acetylcholine (ACh) levels during behavior.

Cortical overgrowth in a preclinical forebrain organoid model of CNTNAP2-associated autism spectrum disorder.

We utilized forebrain organoids generated from induced pluripotent stem cells of patients with a syndromic form of Autism Spectrum Disorder (ASD) with a homozygous protein-truncating mutation in CNTNAP2, to study its effects on embryonic cortical development. Patients with this mutation present with clinical characteristics of brain overgrowth. Patient-derived forebrain organoids displayed an increase in volume and total cell number that is driven by increased neural progenitor proliferation.

How changes in dopamine D2 receptor levels alter striatal circuit function and motivation.

It was first posited, more than five decades ago, that the etiology of schizophrenia involves overstimulation of dopamine receptors. Since then, advanced clinical research methods, including brain imaging, have refined our understanding of the relationship between striatal dopamine and clinical phenotypes as well as disease trajectory. These studies point to striatal dopamine D2 receptors, the main target for all current antipsychotic medications, as being involved in both positive and negative symptoms.

Dopamine D2R upregulation in ventral striatopallidal neurons does not affect Pavlovian or go/no-go learning.

Ventral striatal dopamine is thought to be important for associative learning. Dopamine exerts its role via activation of dopamine D1 and D2 receptors in the ventral striatum. Upregulation of dopamine D2R in ventral striatopallidal neurons impairs incentive motivation via inhibiting synaptic transmission to the ventral pallidum.

Reset of hippocampal-prefrontal circuitry facilitates learning.

The ability to rapidly adapt to novel situations is essential for survival, and this flexibility is impaired in many neuropsychiatric disorders. Thus, understanding whether and how novelty prepares, or primes, brain circuitry to facilitate cognitive flexibility has important translational relevance. Exposure to novelty recruits the hippocampus and medial prefrontal cortex (mPFC) and may prime hippocampal-prefrontal circuitry for subsequent learning-associated plasticity.

Differential Synaptic Dynamics and Circuit Connectivity of Hippocampal and Thalamic Inputs to the Prefrontal Cortex.

The medial prefrontal cortex (mPFC) integrates inputs from multiple subcortical regions including the mediodorsal nucleus of the thalamus (MD) and the ventral hippocampus (vHPC). How the mPFC differentially processes these inputs is not known. One possibility is that these two inputs target discreet populations of mPFC cells.

A device for stereotaxic viral delivery into the brains of neonatal mice.

The increasing interest in manipulating neural circuits in developing brains has created a demand for reliable and accurate methods for delivering viruses to newborn mice. Here we describe a novel 3D-printed mouse neonatal stereotaxic adaptor for intracerebral viral injection that provides enhanced precision and reliability. Using this device, we injected mice with a -dependent hM4D-mCherry viral construct at postnatal day 1 (P1) and demonstrated selective expression in the striatal indirect pathway neurons on days P7, P11 and P25.

Functional and molecular heterogeneity of D2R neurons along dorsal ventral axis in the striatum.

Action control is a key brain function determining the survival of animals in their environment. In mammals, neurons expressing dopamine D2 receptors (D2R) in the dorsal striatum (DS) and the nucleus accumbens (Acb) jointly but differentially contribute to the fine regulation of movement. However, their region-specific molecular features are presently unknown.

Medial prefrontal lesions impair performance in an operant delayed nonmatch to sample working memory task.

Cognitive functions, such as working memory, are disrupted in most psychiatric disorders. Many of these processes are believed to depend on the medial prefrontal cortex (mPFC). Traditionally, maze-based behavioral tasks, which have a strong exploratory component, have been used to study the role of the mPFC in working memory in mice.

Dopamine D2 receptor overexpression in the nucleus accumbens core induces robust weight loss during scheduled fasting selectively in female mice.

Anorexia nervosa (AN) is an eating disorder observed predominantly in women and girls that is characterized by a low body-mass index, hypophagia, and hyperactivity. Activity-based anorexia (ABA), which refers to the weight loss, hypophagia, and hyperactivity exhibited by rodents exposed to both running wheels and scheduled fasting, provides a model for aspects of AN. Increased dopamine D2/D3 receptor binding in the anteroventral striatum has been reported in AN patients.

Regulation of endogenous antigen presentation in response to suboptimal temperatures in a walleye skin fibroblast cell line.

A skin fibroblast cell line WE-skin11f from walleye (Sander vitreus) was used to study the impact of temperature (26 °C, 20 °C, 14 °C, or 4 °C) on the transcript levels of genes involved in the endogenous antigen processing and presentation pathway (EAPP), which is an important antiviral pathway of vertebrates. Partial coding sequences were found for 4 previously unidentified walleye EAPP members, calreticulin, calnexin, erp57, and tapasin, and the constitutive transcript levels of these genes in WE-skin11f was unchanged by culture incubation temperature. The viral mimic poly (I:C) and viral haemorrhagic septicaemia virus (VHSV) IVb were used to study possible induction of EAPP transcripts (b2m, mhIa, and tapasin).

Hippocampal-Prefrontal Theta Transmission Regulates Avoidance Behavior.

Long-range synchronization of neural oscillations correlates with distinct behaviors, yet its causal role remains unproven. In mice, tests of avoidance behavior evoke increases in theta-frequency (∼8 Hz) oscillatory synchrony between the ventral hippocampus (vHPC) and medial prefrontal cortex (mPFC). To test the causal role of this synchrony, we dynamically modulated vHPC-mPFC terminal activity using optogenetic stimulation.

Characterization of the continuous skin fibroblastoid cell line, WE-skin11f, from walleye (Sander vitreus).

A walleye dermal fibroblastoid cell line, WE-skin11f, was established and characterized. WE-skin11f was immunocytochemically positive for two known dermal fibroblast protein markers: vimentin and collagen I. At passage 26, WE-skin11f cultures contained both diploid and aneuploid populations.