Nicotinic regulation of local and long-range input balance drives top-down attentional circuit maturation

Cognitive function depends on frontal cortex development; however, the mechanisms driving this process are poorly understood. Here, we identify that dynamic regulation of the nicotinic cholinergic system is a key driver of attentional circuit maturation associated with top-down frontal neurons projecting to visual cortex. The top-down neurons receive robust cholinergic inputs, but their nicotinic tone decreases following adolescence by increasing expression of a nicotinic brake, Lynx1. Lynx1 shifts a balance between local and long-range inputs onto top-down frontal neurons following adolescence and promotes the establishment of attentional behavior in adulthood. This key maturational process is disrupted in a mouse model of fragile X syndrome but was rescued by a suppression of nicotinic tone through the introduction of Lynx1 in top-down projections. Nicotinic signaling may serve as a target to rebalance local/long-range balance and treat cognitive deficits in neurodevelopmental disorders.

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Adolescent frontal top-down neurons receive heightened local drive to establish adult attentional behavior in mice

10.1101/2020.05.26.117929 ◽

2020 ◽

Author(s):

Elisa M Nabel ◽

Yury Garkun ◽

Hiroyuki Koike ◽

Masato Sadahiro ◽

Ana Liang ◽

...

Keyword(s):

Long Range ◽

Attentional Control ◽

Cortical Neurons ◽

Anterior Cingulate ◽

Sensitive Period ◽

Neuron Activity ◽

Top Down ◽

Local Circuitry ◽

Local Circuits ◽

Attentional Behavior

AbstractFrontal top-down cortical neurons projecting to sensory cortical regions are well-positioned to integrate long-range inputs with local circuitry in frontal cortex to implement top-down attentional control of sensory regions. How adolescence contributes to the maturation of top-down neurons and associated local/long-range input balance, and the establishment of attentional control is poorly understood. Here we combine projection-specific electrophysiological and rabies-mediated input mapping in mice to uncover adolescence as a developmental stage when frontal top-down neurons projecting from the anterior cingulate to visual cortex are highly functionally integrated into local excitatory circuitry and have heightened activity compared to adulthood. Chemogenetic suppression of top-down neuron activity selectively during adolescence, but not later periods, produces long-lasting visual attentional behavior deficits, and results in excessive loss of local excitatory inputs in adulthood. Our study reveals an adolescent sensitive period when top-down neurons integrate local circuits with long-range connectivity to produce attentional behavior.

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Evaluation of acetylcholinesterase activity and behavioural alterations induced by ketamine in an animal model of schizophrenia

Acta Neuropsychiatrica ◽

10.1017/neu.2013.31 ◽

2013 ◽

Vol 26 (1) ◽

pp. 43-50 ◽

Cited By ~ 9

Author(s):

Alexandra I. Zugno ◽

Maria Paula Matos ◽

Leila Canever ◽

Daiane B. Fraga ◽

Renata D. De Luca ◽

...

Keyword(s):

Animal Model ◽

Cognitive Deficits ◽

Cholinergic System ◽

Ache Activity ◽

Cognitive Deficit ◽

Chronic Administration ◽

Inhibitory Avoidance ◽

Acetylcholinesterase Activity ◽

Chronic Effects ◽

Behavioural Tests

ObjectiveCognitive deficits in schizophrenia play a crucial role in its clinical manifestation and seem to be related to changes in the cholinergic system, specifically the action of acetylcholinesterase (AChE). Considering this context, the aim of this study was to evaluate the chronic effects of ketamine in the activity of AChE, as well as in behavioural parameters involving learning and memory.MethodsThe ketamine was administered for 7 days. A duration of 24 h after the last injection, the animals were submitted to behavioural tests. The activity of AChE in prefrontal cortex, hippocampus and striatum was measured at different times after the last injection (1, 3, 6 and 24 h).ResultsThe results indicate that ketamine did not affect locomotor activity and stereotypical movements. However, a cognitive deficit was observed in these animals by examining their behaviour in inhibitory avoidance. In addition, an increase in AChE activity was observed in all structures analysed 1, 3 and 6 h after the last injection. Differently, serum activity of AChE was similar between groups.ConclusionChronic administration of ketamine in an animal model of schizophrenia generates increased AChE levels in different brain tissues of rats that lead to cognitive deficits. Therefore, further studies are needed to elucidate the complex mechanisms associated with schizophrenia.

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Frontal-Sensory Cortical Projections Become Dispensable for Attentional Performance Upon a Reduction of Task Demand in Mice

Frontiers in Neuroscience ◽

10.3389/fnins.2021.775256 ◽

2022 ◽

Vol 15 ◽

Author(s):

Kevin J. Norman ◽

Julia Bateh ◽

Priscilla Maccario ◽

Christina Cho ◽

Keaven Caro ◽

...

Keyword(s):

Reaction Time ◽

Reaction Time Task ◽

Serial Reaction Time Task ◽

Task Demand ◽

Serial Reaction Time ◽

Top Down ◽

Time Task ◽

Attentional Performance ◽

Serial Reaction ◽

Attentional Behavior

Top-down attention is a dynamic cognitive process that facilitates the detection of the task-relevant stimuli from our complex sensory environment. A neural mechanism capable of deployment under specific task-demand conditions would be crucial to efficiently control attentional processes and improve promote goal-directed attention performance during fluctuating attentional demand. Previous studies have shown that frontal top-down neurons projecting from the anterior cingulate area (ACA) to the visual cortex (VIS; ACAVIS) are required for visual attentional behavior during the 5-choice serial reaction time task (5CSRTT) in mice. However, it is unknown whether the contribution of these projecting neurons is dependent on the extent of task demand. Here, we first examined how behavior outcomes depend on the number of locations for mice to pay attention and touch for successful performance, and found that the 2-choice serial reaction time task (2CSRTT) is less task demanding than the 5CSRTT. We then employed optogenetics to demonstrate that suppression ACAVIS projections immediately before stimulus presentation has no effect during the 2CSRTT in contrast to the impaired performance during the 5CSRTT. These results suggest that ACAVIS projections are necessary when task demand is high, but once a task demand is lowered, ACAVIS neuron activity becomes dispensable to adjust attentional performance. These findings support a model that the frontal-sensory ACAVIS projection regulates visual attention behavior during specific high task demand conditions, pointing to a flexible circuit-based mechanism for promoting attentional behavior.

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Fragile X syndrome

InnovAiT Education and inspiration for general practice ◽

10.1177/1755738020958183 ◽

2020 ◽

Vol 13 (12) ◽

pp. 712-716

Author(s):

Rebecca Dunphy

Keyword(s):

Primary Care ◽

Learning Disability ◽

Fragile X Syndrome ◽

Clinical Features ◽

Neurodevelopmental Disorders ◽

Fragile X ◽

Healthcare Services ◽

Diagnosis And Management ◽

Genetic Causes

Fragile X syndrome is one of the most common genetic causes of learning disability. Patients with this and other neurodevelopmental disorders will often present to primary care before a diagnosis is made, and this can be challenging and worrying for patients and other carers. These patients may face a number of barriers in accessing healthcare services including communication, behavioural and sensory difficulties. It may be difficult to understand whether symptoms are part of their condition or because of a comorbidity that needs to be addressed. Input from families and carers can be vital in helping with diagnosis. This article aims to outline the key clinical features, diagnosis and management of this syndrome.

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Specific effect of the fragile-X mental retardation-1 gene (FMR1) on white matter microstructure

The British Journal of Psychiatry ◽

10.1192/bjp.bp.114.151654 ◽

2015 ◽

Vol 207 (2) ◽

pp. 143-148 ◽

Cited By ~ 11

Author(s):

Tamar Green ◽

Naama Barnea-Goraly ◽

Mira Raman ◽

Scott S. Hall ◽

Amy A. Lightbody ◽

...

Keyword(s):

Genetic Variation ◽

Intellectual Disability ◽

White Matter ◽

Neurodevelopmental Disorders ◽

Fragile X ◽

Neurodevelopmental Disorder ◽

Specific Effect ◽

Radial Diffusivity ◽

Fragile X Mental Retardation ◽

White Matter Microstructure

BackgroundFragile-X syndrome (FXS) is a neurodevelopmental disorder associated with intellectual disability and neurobiological abnormalities including white matter microstructural differences. White matter differences have been found relative to neurotypical individuals.AimsTo examine whether FXS white matter differences are related specifically to FXS or more generally to the presence of intellectual disability.MethodWe used voxel-based and tract-based analytic approaches to compare individuals with FXS (n = 40) with gender- and IQ-matched controls (n = 30).ResultsIndividuals with FXS had increased fractional anisotropy and decreased radial diffusivity values compared with IQ-matched controls in the inferior longitudinal, inferior fronto-occipital and uncinate fasciculi.ConclusionsThe genetic variation associated with FXS affects white matter microstructure independently of overall IQ. White matter differences, found in FXS relative to IQ-matched controls, are distinct from reported differences relative to neurotypical controls. This underscores the need to consider cognitive ability differences when investigating white matter microstructure in neurodevelopmental disorders.

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