Research paperAltered corticostriatal synchronization associated with compulsive-like behavior in APP/PS1 mice
Introduction
Alzheimer's disease (AD) patients can develop neuropsychiatric symptoms, such as apathy, changes in response control and emotional dysregulation (Fernández-Martínez et al., 2008; Goukasian et al., 2019; Marchant et al., 2020; Nancy J. Donovan et al., 2018). There is increasing evidence that the mild behavioral impairment (MBI) observed before the onset of cognitive decline may be an early sign of AD. Recent studies have shown that obsessive-compulsive disorder (OCD), which involves obsessive thoughts and compulsive behavior, might be a characteristic of the early stages of AD (Dondu et al., 2015; Moheb et al., 2019). In the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), OCD has been reclassified in a new category of neuropsychiatric disorder and is now known as a transdiagnostic psychiatric trait (Gillan et al., 2016). However, the molecular mechanisms and neural circuits by which mild changes in behavior during presymptomatic AD are mediated remain unclear.
Mounting evidence supports the notion that changes in corticostriatal circuits underlie MBI, typified by changes in emotional and compulsive behavior, which can arise in presymptomatic AD (Abbott et al., 2017; Bentea et al., 2020; Burguière et al., 2015; Manning et al., 2015). The striatum (Str) receives strong inputs from the prefrontal cortex (PFC) as part of the process of integrating cognitive information (Lago et al., 2017; Voorn et al., 2004). Studies in rodents suggest that the role played by Str in regulating aberrant behavior is probably executed in combination with other cortical regions, including PFC and its subregions (Fuccillo, 2016; Martos et al., 2017; Yang et al., 2021). OCD is considered to be a common form of MBI, which is controlled by the interconnectivity between PFC and Str (Anticevic et al., 2014; Harvey et al., 2001; Thompson et al., 2019). For example, Sapap3-mutant mice, a mouse model of OCD, have corticostriatal synaptic defects and also exhibit increased anxiety and compulsive grooming behavior (Welch et al., 2007). Loss of Slitrk5 also results in OCD-like behavior and impaired corticostriatal neurotransmission (Shmelkov et al., 2010). Furthermore, PFC and Str are the first regions of the brain to be affected by amyloid deposition (Lo et al., 2013; Ren et al., 2016), and corticostriatal dysfunction might be relevant to AD-related neurodegeneration. Nevertheless, the molecular mechanisms underlying these symptoms of MBI during presymptomatic AD are not clear.
The oscillatory neural network is linked to multiple types of behavior and performance of cognitive tasks, while regulation of GABA transmission and GABA interneuron excitability is impaired in AD models (Bi et al., 2020; Zhong et al., 2003). Oscillations in the gamma (γ) range are abnormal in a mouse model of AD due to compromised synaptic activity (Etter et al., 2019). Meanwhile, GABAergic inhibition, which modulates oscillatory activity in the γ range (30–100 Hz), can modify symptoms of MBI and affect the excitation-inhibition balance (Egashira et al., 2013; Luo et al., 2020; Sun et al., 2019; Xu et al., 2019). Considering these previous findings, it is of interest to explore whether and how the GABAergic system in corticostriatal circuits modulates aberrant behavior in presymptomatic AD.
In the present study, we evaluated the interconnection of PFC-Str inputs at the cellular and molecular levels in 3–5-month-old APP/PS1 mice with symptoms of MBI. We found distinct changes in striatal oscillations in the beta (β) and high γ (γhigh) ranges, as well as altered synchronization in corticostriatal circuits. Consistent with their aberrant γ rhythms, APP/PS1 mice show increased striatal neuronal activity, decreased numbers of neighboring parvalbumin (PV)-interneurons and reduced GABAergic inhibition, suggesting that molecular changes in corticostriatal circuits mediate aberrant behavior during presymptomatic AD.
Section snippets
Animals
APPswe/PSEN1ΔE9 (APP/PS1) transgenic mice and their wild-type (WT) littermates were obtained from Model Animal Research Center of Nanjing University (Nanjing, China). Regardless of sex, 3–5-month-old APP/PS1 mice and WT littermates were used in this study and housed individually in accordance with the guidelines of the National Institutes of Health on animal care and the ethical guidelines of the Ethics Committee for Animal Research at South China Normal University as follows. Mice were housed
Aberrant behavior in 3–5-month-old APP/PS1 mice
It has previously been shown that MBI is an early marker of AD, occurring before cognitive decline and dementia in individuals with normal cognition, and is associated with higher risk of AD in the later-life (Ismail et al., 2017). MBI includes behavioral problems that persist for at least 6 months, such as emotional dysregulation and dyscontrol (Creese et al., 2019). Here, we tested the hypothesis that abnormal behavior occurs in 3–5-month-old APP/PS1 mice. Burying marbles, nestlet shredding
Discussion
Failure to cope with stress or conflict in daily life is associated with abnormal repetitive behavior, which are typical symptoms of MBI (Dillon et al., 2013). Recent studies in rodents report that compulsive behavior is exhibited at different stages of the AD process (Ortega-Martinez et al., 2019; Shepherd et al., 2021). In the present study, we demonstrate compulsive behavior in 3–5-month-old APP/PS1 mice, prior to the onset of disease symptoms in this AD model mouse strain, as evidenced by
Conflict of interests
The authors declare that there are no competing financial interests.
Author contributions
Yi-gang Peng: Investigation, Formal analysis, Visualization. Ping-jing Cai: Investigation, Visualization. Jian-hang Hu: Investigation, Formal analysis. Jin-xiang Jiang: Software, Formal analysis, Visualization, Writing- Original draft preparation. Jia-jia Zhang: Investigation. Ke-fang Liu: Investigation. Li Yang: Supervision, Project administration, Funding acquisition. Cheng Long: Conceptualization, Supervision, Writing – Review and Editing, Funding acquisition..
Acknowledgements
The present study was supported by grants from the National Natural Science Foundation of China (31771219, 31871170, 31970915), the Natural Science Foundation of Guangdong Province (2021A1515010804), the Guangdong Natural Science Foundation for Major Cultivation Project (2018B030336001) and the Guangdong Grant ‘Key Technologies for Treatment of Brain Disorders' (2018B030332001).
References (95)
- et al.
Global resting-state functional magnetic resonance imaging analysis identifies frontal cortex, striatal, and cerebellar dysconnectivity in obsessive-compulsive disorder
Biol. Psychiatry
(2014) - et al.
Striatal circuits, habits, and implications for obsessive-compulsive disorder
Curr. Opin. Neurobiol.
(2015) - et al.
Mild behavioral impairment as a marker of cognitive decline in cognitively normal older adults
Am. J. Geriatr. Psychiatry
(2019) - et al.
Is obsessive–compulsive symptomatology a risk factor for Alzheimer-type dementia?
Psychiatry Res.
(2015) - et al.
Presupplementary motor area contributes to altered error monitoring in obsessive-compulsive disorder
Biol. Psychiatry
(2016) - et al.
Microglial activation in the dorsal striatum participates in anxiety-like behavior in Cyld knockout mice
Brain Behav. Immun.
(2020) - et al.
Chronic inositol increases striatal D(2) receptors but does not modify dexamphetamine-induced motor behavior. Relevance to obsessive-compulsive disorder
Pharmacol. Biochem. Behav.
(2001) - et al.
The gamma-aminobutyric acid B receptor in depression and reward
Biol. Psychiatry
(2018) - et al.
Exposure to prenatal antidepressant alters medial prefrontal-striatal synchronization in mice
Brain Res.
(2019) - et al.
Deficits in the activity of presynaptic γ-aminobutyric acid type B receptors contribute to altered neuronal excitability in fragile X syndrome
J. Biol. Chem.
(2017)
Glutamatergic and gabaergic postsynaptic responses of striatal spiny neurons to intrastriatal and cortical stimulation recorded in slice preparations
Neuroscience
Striatum on the anxiety map: small detours into adolescence
Brain Res.
Erbin in amygdala parvalbumin-positive neurons modulates anxiety-like behaviors
Biol. Psychiatry
Seizure susceptibility in the APP/PS1 mouse model of Alzheimer’s disease and relationship with amyloid beta plaques
Brain Res.
The nucleus accumbens: a target for deep brain stimulation in obsessive-compulsive- and anxiety-disorders
J. Chem. Neuroanat.
Putting a spin on the dorsal–ventral divide of the striatum
Trends Neurosci.
Dynamic network communication as a unifying neural basis for cognition, development, aging, and disease
Biol. Psychiatry
Memantine rescues prenatal citalopram exposure-induced striatal and social abnormalities in mice
Exp. Neurol.
The mechanisms underlying olfactory deficits in apolipoprotein E-deficient mice: focus on olfactory epithelium and olfactory bulb
Neurobiol. Aging
Impaired modulation of GABAergic transmission by muscarinic receptors in a mouse transgenic model of Alzheimer’s disease
J. Biol. Chem.
Repetitive behaviors in autism are linked to imbalance of corticostriatal connectivity: a functional connectivity MRI study
Soc. Cogn. Affect. Neurosci.
Repeated cortico-striatal stimulation generates persistent OCD-like behavior
Science
GABAB receptor-mediated, layer-specific synaptic plasticity reorganizes gamma-frequency neocortical response to stimulation
Proc. Natl. Acad. Sci. U. S. A.
A critical period for antidepressant-induced acceleration of neuronal maturation in adult dentate gyrus
Transl. Psychiatry
Striatal microstimulation induces persistent and repetitive negative decision-making predicted by striatal Beta-band oscillation
Neuron
Increased soluble amyloid-beta causes early aberrant brain network hypersynchronisation in a mature-onset mouse model of amyloidosis
Acta Neuropathol. Commun.
Corticostriatal dysfunction and social interaction deficits in mice lacking the cystine/glutamate antiporter
Mol. Psychiatry
GABAergic dysfunction in excitatory and inhibitory (E/I) imbalance drives the pathogenesis of Alzheimer’s disease
Alzheimers Dement.
Presynaptic GABAB receptors functionally uncouple somatostatin interneurons from the active hippocampal network
eLife
Optogenetic stimulation of lateral orbitofronto-striatal pathway suppresses compulsive behaviors
Science
Striatal circuits, habits, and implications for obsessive–compulsive disorder
Curr. Opin. Neurobiol.
Driving fast-spiking cells induces gamma rhythm and controls sensory responses
Nature
A biophysical model of striatal microcircuits suggests gamma and beta oscillations interleaved at delta/theta frequencies mediate periodicity in motor control
PLoS Comput. Biol.
Distinct inhibitory circuits orchestrate cortical beta and gamma band oscillations
Neuron
Distinct inhibitory circuits orchestrate cortical beta and gamma band oscillations
Neuron
APP modulates KCC2 expression and function in hippocampal GABAergic inhibition
eLife
Enhancing GABAergic signaling ameliorates aberrant gamma oscillations of olfactory bulb in AD mouse models
Mol. Neurodegener.
Strengthened inputs from secondary motor cortex to striatum in a mouse model of compulsive behavior
J. Neurosci.
Behavioral symptoms related to cognitive impairment
Neuropsychiatr. Dis. Treat.
Longitudinal association of amyloid beta and anxious-depressive symptoms in cognitively normal older adults
Am. J. Psychiatr.
GABA(B) autoreceptor-mediated cell type-specific reduction of inhibition in epileptic mice
Proc. Natl. Acad. Sci. U. S. A.
Effects of mood stabilizers on marble-burying behavior in mice
Psychopharmacology
Optogenetic gamma stimulation rescues memory impairments in an Alzheimer’s disease mouse model
Nat. Commun.
Mouse hippocampal GABAB1 but not GABAB2 subunit-containing receptor complex levels are paralleling retrieval in the multiple-T-maze
Front. Behav. Neurosci.
Prevalence of neuropsychiatric symptoms in Alzheimer’s disease and vascular dementia
Curr. Alzheimer Res.
Cortico-striatal-thalamic loop circuits of the orbitofrontal cortex: promising therapeutic targets in psychiatric illness
Front. Syst. Neurosci.
Cortical GABAergic dysfunction in stress and depression: new insights for therapeutic interventions
Front. Cell. Neurosci.
Cited by (9)
Compulsive-like Behaviors in Amyloid-β 1-42–Induced Alzheimer's Disease in Mice Are Associated With Hippocampo-cortical Neural Circuit Dysfunction
2023, Biological Psychiatry Global Open ScienceTheta and gamma oscillatory dynamics in mouse models of Alzheimer's disease: A path to prospective therapeutic intervention
2022, Neuroscience and Biobehavioral ReviewsCitation Excerpt :The correlation between this hyperexcitability and cognitive impairment in AD may be further associated with disruptions in hippocampal rhythmic activity (Wang et al., 2020). Additionally, oscillatory activity within the entorhinal cortex (EC) (Klein et al., 2016; Nakazono et al., 2017; Ridler et al., 2020), prefrontal cortex (PFC) (Ahnaou et al., 2017; Bazzigaluppi et al., 2018; Peng et al., 2021) and olfactory bulb (OB) (Ahnaou et al., 2020; Chen et al., 2021) are also seen to undergo alterations in AD mouse models that recapitulate, at least partially, the neuropathology of human AD. In this regard, numerous investigations have reported that transgenic mouse models of AD exhibit significant abnormalities in brain networks (Busche and Konnerth, 2015; Palop et al., 2007; Palop and Mucke, 2010), similar to the alterations observed in human AD (Nimmrich et al., 2015).
Identification of IGF-1 Effects on White Adipose Tissue and Hippocampus in Alzheimer’s Disease Mice via Transcriptomic and Cellular Analysis
2024, International Journal of Molecular SciencesAberrant Cortical Activity in 5xFAD Mice in Response to Social and Non-Social Olfactory Stimuli
2024, Journal of Alzheimer's DiseaseDistinct ACC neural mechanisms underlie authentic and transmitted anxiety induced by maternal separation in mice
2023, Journal of NeuroscienceNeural mechanism underlies CYLD modulation of morphology and synaptic function of medium spiny neurons in dorsolateral striatum
2023, Frontiers in Molecular Neuroscience