Habituation to repeatedly presented stimuli is a prerequisite to adapting to the environment and is, often, reduced in patients with autism spectrum disorder (ASD), which may account for social impairments. However, the brain circuitry, regulators and the molecular mechanisms involved in habituation are poorly understood.

Now, investigators led by Runa Hamid from the Council of Scientific and Industrial Research-Centre for Cellular and Molecular Biology (CSIR-CCMB) laboratory in Hyderabad, India, have identified a transporter protein in the brain that plays a vital role in habituation. The authors published their work online on December 16, 2021, in the journal PLoS Genetics.

Hamid is a Department of Science & Technology (DST), Principal Investigator at CCMB and is involved in the study of brain functions like learning and memory in fruit flies.

Hamid's team found that the choline transporter, a protein that imports choline into neurons so that cells can produce the neurotransmitter acetylcholine, regulates odor habituation. Fruit flies that showed low levels of choline transporters in certain parts of the brain did not get used to a scent and instead became hypersensitive.

Previously, Hamid and her colleagues had reported a high level of the choline transporter in the memory processing and storing region of the fruit fly brain called mushroom bodies. These findings led them to study a putative role of the choline transporter in habituation, which is widely regarded as a prerequisite for more complex forms of associative learning.

Speaking to BioWorld Science, Hamid said that "We used olfaction-based habituation paradigms for the study and observed that defective habituation due to knockdown of the choline transporter in fruit fly larval mushroom bodies is accompanied by hypersensitivity towards an attractive odor."

In the study, the authors further show that external depletion of the transporter in neurons of the olfactory pathway leads to defective habituation but does not cause hypersensitivity towards an attractive odor. According to Hamid, "these results suggest that mushroom bodies are an important site through which the choline transporter regulates incoming stimulus suppression."

Interestingly, the study also indicates that the conserved choline transporter protein is not unique to cholinergic neurons but is also required by GABAergic neurons to drive habituation behavior as seen by the knockdown of the transporter in GABAergic neurons leading to hypersensitivity towards an attractive odor. Hamid adds that "Our results support a model in which the choline transporter regulates both habituation and incoming stimuli through a neural circuit that includes excitatory, inhibitory and mushroom body neurons."

The hypersensitivity and other changes observed in the flies with fewer choline transporters are similar to symptoms seen in people with ASD. Additionally, previous work has shown that variations in the choline transporter have been associated with other neurological disorders like attention deficit hyperactivity disorder (ADHD).

The study's findings open new avenues for future research to explore the role of choline transporters in disorders related to habituation and further studies on habituation mechanisms in diverse models can facilitate the delineation of affected cognitive domains that may correlate with or arise from deficient habituation in neurodevelopmental disorders. Understanding the underlying defective mechanisms in Drosophila can also identify novel targets for treatment.

Hamid added, "Our study brings to the fore a hitherto unknown function of the choline transporter. It gives an insight into the mechanism of habituation, a conserved phenomenon across the animal kingdom that enables an organism to focus attention only on salient sensory stimuli in the surroundings and ignore inconsequential stimuli. This work may have far-reaching implications for our understanding of several neurological disorders."