Biology subjects

Abdulla, Z. I.

Publications and source records attributed to Abdulla, Z. I..

3 recordsLinked to original sources

bioRxiv2026

mPFC Synaptosome Proteomics Reveals Novel Pathways and Muscarinic Receptor Changes in a Learned Helplessness Mouse Model

Stressful events are a leading factor in development of depression. The medial prefrontal cortex (mPFC) is strongly associated with depression etiology and exposure to uncontrollable stressors results in synaptic dysfunction and loss. Learned helplessness is a behavioral paradigm that measures effects of repeated exposure to uncontrollable, inescapable stress on later responses to escapable stress. We therefore performed a proteomic analysis of mPFC synaptosomes in a mouse learned helplessness model to identify molecular changes that could contribute to functional consequences of inescapable stress. Male and female mice were evaluated at baseline and following exposure to escapable or inescapable stress followed by an active avoidance test. Label-free mass spectrometry followed by pathway and protein-protein interaction network analyses identified alterations in signaling pathways involved in energy metabolism, neurotransmitter signaling, and protein shuttling. Furthermore, phosphoproteomics revealed alterations related to synaptic function, neurotransmitter signaling and protein internalization, as well as changes in activity of kinases previously identified as mediators of antidepressant efficacy (GSK3B) and receptor internalization (ADRBK1). We more deeply examined alterations in the Acetylcholine Receptor Signaling Pathway, and identified muscarinic receptor proteins (Chrm1, Chrm2, Chrm4) and key proteins involved in their translocation to and from the membrane. These results identify substantial changes in the mPFC proteome following exposure to inescapable stressors. In addition, mPFC muscarinic cholinergic signaling is well placed to mediate responses to an inescapable stressor. This proteomic study will be useful in guiding studies of human mPFC relevant to depression. Data are available via ProteomeXchange with identifier PXD073765.

neuroscience↗

bioRxiv2023

Acetylcholine signaling in the medial prefrontal cortex mediates the ability to learn an active avoidance response following learned helplessness training

Increased brain levels of acetylcholine (ACh) are observed in subsets of patients with depression and increasing ACh levels chronically can precipitate stress-related behaviors in humans and animals. Conversely, optimal ACh levels are required for cognition and memory. We hypothesize that ACh signaling is important for encoding both appetitive and stress-relevant memories, but that excessive increases in ACh result in a negative encoding bias in which memory formation of a stressful event is aberrantly strengthened, potentially contributing to the excessive focus on negative experience that could lead to depressive symptoms. The medial prefrontal cortex (mPFC) is critical to control the limbic system to filter exteroceptive cues and stress-related circuits. We therefore evaluated the role of ACh signaling in the mPFC in a learned helplessness task in which mice were exposed to repeated inescapable stressors followed by an active avoidance task. Using fiber photometry with a genetically-encoded ACh sensor, we found that ACh levels in the mPFC during exposure to inescapable stressors were positively correlated with later escape deficits in an active avoidance test in males, but not females. Consistent with these measurements, we found that both pharmacologically- and chemogenetically-induced increases in mPFC ACh levels resulted in escape deficits in both male and female mice, whereas chemogenetic inhibition of ACh neurons projecting to the mPFC improved escape performance in males, but impaired escape performance in females. These results highlight the adaptive role of ACh release in stress response, but also support the idea that sustained elevated ACh levels contribute to maladaptive behaviors. Furthermore, mPFC ACh signaling may contribute to depressive symptomology differentially in males and females.

neuroscience↗

bioRxiv2018

Deletion of the Creatine Transporter in dopaminergic neurons leads to hyperactivity in mice.

Creatine (Cr) is required for proper neuronal function, as evidenced by the intellectual disability and epileptic phenotype seen in patients with cerebral Cr deficiency syndromes (CCDS). In addition, attention-deficit hyperactivity disorder (ADHD) is a frequent co-morbidity of Cr transporter (Crt) deficiency, the leading cause of CCDS. While the effects of the loss of Cr in the whole brain is clear, it is unknown if Cr is required for the proper function of all neurons. Of particular interest are dopaminergic neurons, as many CCDS patients have ADHD and Cr has been implicated in dopamine-associated neurodegenerative disorders, such as Parkinsons and Huntingtons diseases. The purpose of this study was to examine the effect of a loss of the Slc6a8 (Cr transporter; Crt) gene in cells expressing the dopamine transporter (Slc6a3; DAT) on activity levels and motor function as the animals age. DAT-specific Crt-knockout (DAT-Crt) mice were tested along with control (Crt-FLOX) mice monthly from 3 to 12 months of age in locomotor activity, the challenging beam test, and spontaneous activity. DAT-Crt mice were hyperactive compared with controls and this finding persisted throughout the lifetime of the mice. No changes were observed in errors to cross a narrow bridge in the challenging beam test. In a measurement of spontaneous activity, DAT-Crt mice showed increased rearing and hind limb steps, suggesting the hyperactivity carried over to this task. Taken together, these data suggest that the lack of Cr in dopaminergic neurons causes hyperactivity while sparing motor function.\n\nAbbreviations

neuroscience↗