Parkinson's disease (PD) is linked to several genetic loci (PARK genes), many affecting dopamine signaling. Non-motor symptoms like apathy and motivational disturbances often precede motor symptoms. *SYNJ1* (PARK20) encodes synaptojanin1, crucial for neurotransmission and synaptic vesicle recycling. Previous research showed that while homozygous deletion of *Synj1* is lethal, heterozygous deletion (*Synj1^+/-*) in mice impairs motor coordination, reduces striatal dopaminergic terminals, and increases α-synuclein accumulation—a PD hallmark. *SYNJ1* is also implicated in autism, bipolar disorder, and schizophrenia. Dopamine system malfunction in PD is associated with motivational deficits. A recent study showed a Synaptojanin1-sensitive dopamine transporter (DAT) internalization process influenced by *Synj1*. This study aims to comprehensively characterize motivation in *Synj1^+/-* mice using tests evaluating locomotor, exploratory, effort-related motivation, and drug reward responses to understand the broader role of *SYNJ1* in motivated behavior and potential deficits in goal-directed behaviors.

The literature review section highlights the established role of *SYNJ1* in dopamine-related disorders and its influence on synaptic vesicle recycling. It emphasizes the existing knowledge gap regarding *SYNJ1*'s impact on motivated behavior and reward processing within the mesolimbic dopamine system. Studies on the link between *SYNJ1* mutations and other neuropsychiatric disorders such as autism, bipolar disorder, and schizophrenia, are reviewed. The authors mention their prior work demonstrating impaired motor coordination, reduced striatal dopaminergic terminals, and increased α-synuclein accumulation in *Synj1^+/-* mice. The connection between dopamine system malfunction and motivational deficits in PD is also discussed, leading to the hypothesis that *SYNJ1* may have a broader role in motivated behavior and goal-directed actions.

The study used 77 *Synj1^+/-* and *Synj1^+/+* littermate mice (24 *Synj1^+/-* males, 11 *Synj1^+/-* females, 29 *Synj1^+/+* males, and 13 *Synj1^+/+* females) aged 6–8 months. Mice underwent a series of behavioral tests in a specific order: elevated plus maze & open field assay (day 1), sucrose preference test (days 2–5), operant conditioning paradigm (days 6–20), progressive ratio-schedule task (day 21), and cocaine conditioned place (CPP) preference paradigm with a drug-primed reinstatement test (days 22–33). A separate cohort was used for an object location memory task (1–8 days) to control for the CPP paradigm. The elevated plus maze assessed anxiety-related behavior. The open field test measured locomotor activity. The sucrose preference test evaluated hedonic responses to sucrose. Operant conditioning and the progressive ratio task assessed reward learning and effort-related motivation. The CPP paradigm evaluated the rewarding effects of cocaine. The object location memory task assessed spatial memory. Fiber-photometry recordings using dLight1.2 in the nucleus accumbens measured dopamine signaling in response to ascending cocaine doses (0, 10, 15, and 20 mg/kg). Western blot analysis quantified dopamine transporter (DAT) levels in the midbrain and striatum after saline or cocaine treatment. Statistical analyses included one-way, two-way, and three-way ANOVAs or generalized linear models.

1. *Synj1^+/-* mice showed normal exploratory behaviors and behavioral avoidance in the elevated plus maze and open field. 2. *Synj1^+/-* mice exhibited normal hedonic responses to sucrose. 3. *Synj1^+/-* male mice showed increased motivation for sucrose reward in the FR3 schedule task. 4. Male *Synj1^+/-* mice displayed an attenuated conditioned place preference for cocaine, not due to spatial memory deficits. 5. Both male and female *Synj1^+/-* mice showed delayed peak dopamine release in the nucleus accumbens after cocaine administration. Female *Synj1^+/-* mice also showed slower decay in accumbens dopamine, possibly linked to DAT responses. 6. Male *Synj1^+/-* mice showed impaired adaptive changes in DAT expression in response to repeated cocaine exposure, unlike *Synj1^+/+* males. Cocaine typically increases DAT expression in males, but this was absent in male *Synj1^+/-* mice, who already had elevated baseline striatal DAT.

The findings indicate that *SYNJ1* haploinsufficiency doesn't globally impair reward processing or motivation but produces specific deficits when the dopaminergic system is challenged (e.g., by cocaine). The delayed dopamine kinetics in *Synj1^+/-* mice, particularly the prolonged time to reach peak dopamine levels, suggest underlying dopaminergic system dysfunction. The sex differences observed highlight the complexity of *SYNJ1*'s role and its interaction with sex-specific factors influencing dopamine signaling. The impaired adaptive changes in DAT expression in male *Synj1^+/-* mice further support the idea that *SYNJ1* mutations lead to maladaptive responses to stimulant drugs. This research suggests that focusing on restoring vesicular trafficking and synaptic function could be a more effective therapeutic approach than dopamine replacement therapies alone.

This study demonstrates that *SYNJ1* haploinsufficiency leads to subtle but significant alterations in mesolimbic dopamine signaling, particularly in response to cocaine. The sex-specific differences observed underscore the complexity of dopamine system function and highlight the need for sex-specific therapeutic interventions. Targeting synaptic function and vesicular trafficking might be a more effective strategy for treating *SYNJ1*-related disorders than simply replacing dopamine.

The study focused on relatively young mice (6–8 months old), which may not fully capture the age-related motor impairments seen in *SYNJ1* mutations. The study primarily used males and females. Future research should explore a wider age range and assess more diverse cohorts to better understand the full scope of *SYNJ1* deficiency's effects. Further investigation is needed to fully elucidate the mechanisms underlying the sex differences observed in DAT expression and dopamine kinetics.