Biology subjects

Dalley, J.

Publications and source records attributed to Dalley, J..

4 recordsLinked to original sources

bioRxiv2022

Neurobehavioral precursors of compulsive cocaine-seeking in dual fronto-striatal circuits

Only some individuals using drugs recreationally eventually become addicted, and persist in drug seeking and taking despite adverse consequences. The neurobehavioral determinants of this individual vulnerability have not been fully elucidated. We report that in drug naive rats the future tendency to develop compulsive cocaine seeking is characterised by behavioral stickiness-related functional hypoconnectivity between the prefrontal cortex and posterior dorsomedial striatum in combination with impulsivity-related structural alterations in the infralimbic cortex, anterior insula and nucleus accumbens. These findings show that the vulnerability to develop compulsive cocaine seeking behavior stems from pre-existing structural or functional changes in two distinct cortico-striatal systems that underlie deficits in impulse control and goal-directed behavior.

neuroscience↗

bioRxiv2020

CSPα reduces aggregates and rescues striatal dopamine release in αsynuclein transgenic mice

Synuclein aggregation at the synapse is an early event in Parkinsons disease and is associated with impaired striatal synaptic function and dopaminergic neuronal death. The cysteine string protein (CSP) and synuclein have partially overlapping roles in maintaining synaptic function and mutations in each cause neurodegenerative diseases. CSP is a member of the DNAJ/HSP40 family of co-chaperones and like synuclein, chaperones the SNARE complex assembly and neurotransmitter release. Synuclein can rescue neurodegeneration in CSPKO mice. However, whether synuclein aggregation alters CSP expression and function is unknown. Here we show that synuclein aggregation at the synapse induces a decrease in synaptic CSP and a reduction in the complexes that CSP forms with HSC70 and STGa. We further show that viral delivery of CSP rescues in vitro the impaired vesicle recycling in PC12 cells with synuclein aggregates and in vivo reduces synaptic synuclein aggregates restoring normal dopamine release in 1-120hsyn mice. These novel findings reveal a mechanism by which synuclein aggregation alters CSP at the synapse, and show that CSP rescues synuclein aggregation-related phenotype in 1-120hsyn mice similar to the effect of synuclein in CSPKO mice. These results implicate CSP as a potential therapeutic target for the treatment of early-stage PD.

neuroscience↗

bioRxiv2018

Depopulation of α-synuclein aggregates is associated with rescue of dopamine neuron dysfunction and death in a new Parkinson disease model

Parkinsons Disease (PD) is characterized by the presence of -synuclein aggregates known as Lewy bodies and Lewy neurites, whose formation is linked to disease development. The causal relation between -synuclein aggregates and PD is not well understood. We generated a new transgenic mouse line (MI2) expressing human, aggregation-prone truncated 1-120 -synuclein under the control of the tyrosine hydroxylase promoter. MI2 mice exhibit progressive aggregation of -synuclein in dopaminergic neurons of the substantia nigra pars compacta and their striatal terminals. This is associated with a progressive reduction of striatal dopamine release, reduced striatal innervation and significant nigral dopaminergic nerve cell death starting from 6 and 12 months of age, respectively. Overt impairment in motor behavior was found in MI2 mice at 20 months of age, when 50% of dopaminergic neurons are lost. These changes were associated with an increase in the number and density of 20-500nm -synuclein species as shown by dSTORM. Treatment with the oligomer modulator anle138b, from 9-12 months of age, restored striatal dopamine release and prevented dopaminergic cell death. These effects were associated with a reduction of the inner density of -synuclein aggregates and an increase in dispersed small -synuclein species as revealed by dSTORM. The MI2 mouse model recapitulates the progressive dopaminergic deficit observed in PD, showing that early synaptic dysfunction precedes dopaminergic axonal loss and neuronal death that become associated with a motor deficit upon reaching a certain threshold. Our data also provide new mechanistic insight for the effect of anle138bs function in vivo supporting that targeting -synuclein aggregation is a promising therapeutic approach for PD.

neuroscience↗

bioRxiv2017

mTORC1 in AGRP neurons integrates exteroceptive and interoceptive food-related cues in the modulation of adaptive energy expenditure in mice

Energy dissipation through interscapular brown adipose tissue (iBAT) thermogenesis is an important contributor to adaptive energy expenditure. However, it remains unresolved how acute and chronic changes in energy availability are detected by the brain to adjust iBAT activity and maintain energy homeostasis. Here we provide evidence that AGRP inhibitory tone to iBAT represents an energy-sparing circuit that integrates environmental food cues and internal signals of energy availability. We establish a role for the nutrient-sensing mTORC1 signaling pathway within AGRP neurons in the detection of environmental food cues and internal signals of energy availability, and in the bi-directional control of iBAT thermogenesis during nutrient deficiency and excess. Collectively, our findings provide insights into how mTORC1 signaling within AGRP neurons surveys energy availability to engage iBAT thermogenesis, and identify AGRP neurons as a neuronal substrate for the coordination of energy intake and adaptive expenditure under varying physiological and environmental contexts.

neuroscience↗