Hyper BOLD Activation in Dorsal Raphe Nucleus of APP/PS1 Alzheimer’s Disease Mouse during Reward-Oriented Drinking Test under Thirsty Conditions

Abstract

Alzheimer's disease (AD), a neurodegenerative disease, causes behavioural abnormalities such as disinhibition, impulsivity, and hyperphagia. preclinical studies using AD model mice have investigated these phenotypes by measuring brain activity in awake, behaving mice. in this study, we monitored the behavioural alterations of impulsivity and hyperphagia in middle-aged AD model mice. As a behavioural readout, we trained the mice to accept a water-reward under thirsty conditions. to analyse brain activity, we developed a measure for licking behaviour combined with visualisation of whole brain activity using awake fMRI. In a water-reward learning task, the AD model mice showed significant hyperactivity of the dorsal raphe nucleus in thirsty conditions. in summary, we successfully visualised altered brain activity in AD model mice during reward-oriented behaviour for the first time using awake fMRi. this may help in understanding the causes of behavioural alterations in AD patients.Fifty million people worldwide currently suffer from dementia. This number is estimated to reach 130 million by 2050. Alzheimer's disease (AD) is a neurodegenerative disease accounting for 60-70% of dementia cases 1 . AD develops through amnestic mild cognitive impairment (MCI), in which a decrease of memory function is the only symptom can be recognised. Once dementia develops, memory and various cognitive functions decrease, behavioural and psychological symptoms of dementia (BPSP) are also exhibited 1-3 . As these symptoms progress, it becomes impossible to maintain an independent daily life. Dementia patients mostly need medical care due to BPSP rather than reducing of memory and cognitive functions. BPSP includes depression, anxiety, and apathy. Although research on these BPSP symptoms has progressed, however, most symptoms such as disinhibition, impulsivity and hyperphagia have not been analysed in the way of pathology.AD significantly impairs reward-based behaviour (by 15-20%) in patients. A typical example is hyperphagia, which stems from a lack of satiety control, similar to disorders of impulsivity and compulsivity 4,5 . The Urgency, lack of Perseverance, lack of Premeditation, Sensation Seeking (UPPS) Scale or Barrat's Impulsiveness Scale (BIS) are now used to test for impulsivity in AD patients 3 . Overeating and impulsivity have also recently been reported in AD model mice 6,7 . These observations suggest that AD mice models may be useful in studying hyperphagia and early changes in impulsive behaviour. It has also been suggested that the brainstem serotonergic system, including the dorsal raphe nucleus 8,9 and ventral temporal lobe (hippocampus, parahippocampus, amygdala), are involved in such alterations. However, the neurological mechanisms behind these phenotypes have not yet been identified. In order to elucidate these mechanistic underpinnings, direct evaluation of brain activity associated with abnormal behaviour phenotypes is required 10 .Functional magnetic resonance imaging (fMRI) is widely used in neuroscience resea...

Relationship between elevated impulsivity and cognitive declines in elderly community-dwelling individuals

“…Both clinical 20 – 22 and animal studies 23 – 25 have suggested the implication of serotonergic neurons at the dorsal raphe nucleus in the pathophysiology of impulsivity in the series of histochemical analyses showed the degeneration of serotonergic neurons in some of AD patients 26 – 31 . The accumulation of senile plaques and phosphorylated tau has been also reported to be seen in the damaged raphe nucleus in the AD brain 26 , 31 , and elevated impulsivity was observed in transgenic mouse models of AD 25 , 32 – 35 .…”

“…Both clinical [20][21][22] and animal studies [23][24][25] have suggested the implication of serotonergic neurons at the dorsal raphe nucleus in the pathophysiology of impulsivity in the series of histochemical analyses showed the degeneration of serotonergic neurons in some of AD patients [26][27][28][29][30][31] . The accumulation of senile plaques and phosphorylated tau has been also reported to be seen in the damaged raphe nucleus in the AD brain 26,31 , and elevated impulsivity was observed in transgenic mouse models of AD 25,[32][33][34][35] . More specifically, alterations in the activity of the dorsal raphe nucleus as well as the degeneration of serotonergic neurons at the dorsal raphe nucleus has been detected in an AD mouse model of APPswe/PSEN1dE9 25,35,36 .…”

“…The accumulation of senile plaques and phosphorylated tau has been also reported to be seen in the damaged raphe nucleus in the AD brain 26,31 , and elevated impulsivity was observed in transgenic mouse models of AD 25,[32][33][34][35] . More specifically, alterations in the activity of the dorsal raphe nucleus as well as the degeneration of serotonergic neurons at the dorsal raphe nucleus has been detected in an AD mouse model of APPswe/PSEN1dE9 25,35,36 . Therefore, the serotonergic system is considered to be a potential therapeutic target for AD patients 23,37,38 .…”

Olfactory neuropathology in Alzheimer's disease: a sign of ongoing neurodegeneration

“…The OB receives serotonergic projections from brainstem raphe nuclei that could form a reciprocal pathway that receives down-top signals through the olfactory cortex and modulates OSNs’ synaptic activity ( 50 ). Given theories that emphasize the brainstem’s role in AD pathology, raphe-OB connections could play a key function in AD pathology ( 51 ), because raphe pathology happens at early AD stages ( 52 ), implying that the OB is also involved in an early stage from both anterograde and retrograde influences. According to several other studies, the OB could deliver misfolded proteins into the brain.…”

Single and Combined Neuroimaging Techniques for Alzheimer’s Disease Detection

“…So, with gathering different parts of the brain, brain structure will be revealed, and with different actions in the body like the movement of arms or feet, different parts of the brain will be activated and can be seen in the fMRI scans. e use of fMRI scans for AD detection was widely used last decade [22,23]. A different part of brain activity can be discriminated even from a different view with this image.…”