ORCID Profile
0000-0002-3794-1782
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Central Nervous System | Biological Psychology (Neuropsychology, Psychopharmacology, Physiological Psychology) | Psychology
Nervous System and Disorders | Expanding Knowledge in the Biological Sciences |
Publisher: Cold Spring Harbor Laboratory
Date: 11-05-2023
DOI: 10.1101/2023.05.11.540316
Abstract: The phospholipid and free fatty acid (FFA) composition of neuronal membranes plays a crucial role in learning and memory, but the mechanisms through which neuronal activity affects the brain’s lipid landscape remain largely unexplored. Saturated FFAs, particularly myristic acid (C14:0), strongly increase during neuronal stimulation and memory acquisition, suggesting the involvement of phospholipase A1 (PLA1) activity in synaptic plasticity. Here, we show that genetic ablation of the DDHD2 isoform of PLA1 in mice reduced memory performance in reward-based learning and spatial memory models prior to the development of neuromuscular deficits, and markedly reduced saturated FFAs across the brain. DDHD2 was shown to bind to the key synaptic protein STXBP1. Using STXBP1/2 knockout neurosecretory cells and a haploinsufficient STXBP1 +/- mouse model of STXBP1 encephalopathy that is also associated with intellectual disability and motor dysfunction, we show that STXBP1 controls the targeting of DDHD2 to the plasma membrane and the generation of saturated FFAs in the brain. Our findings suggest key roles for DDHD2 and STXBP1 in the lipid metabolism underlying synaptic plasticity, learning and memory.
Publisher: EMBO
Date: 11-12-2018
Publisher: Public Library of Science (PLoS)
Date: 17-06-2016
Publisher: Elsevier BV
Date: 10-2021
Publisher: Cold Spring Harbor Laboratory
Date: 22-03-2021
DOI: 10.1101/2021.03.22.436417
Abstract: Psychostimulants such as hetamine target dopamine neuron synapses to engender drug-induced plasticity. While dopamine neurons modulate the activity of striatal cholinergic interneurons (ChIs) with regional heterogeneity, how hetamine affects ChI activity has not been elucidated. Here, we applied quantitative fluorescence imaging approaches to map the dose-dependent effects of a single dose of hetamine on ChI activity at 2.5 and 24 hours after injection across the mouse striatum using the activity-dependent marker phosphorylated ribosomal protein S6 (p-rpS6). We found that hetamine did not induce neurotoxic effects on ChIs, as their distribution and morphology were not affected. While low- or high-dose hetamine did not affect ChI activity after 2.5 hours, ChI activity was significantly reduced in all striatal subregions after 24 hours, with a dose-dependent effect in the nucleus accumbens. Thus, our findings suggest that a single dose of hetamine has delayed regionally heterogeneous effects on ChI activity. Using the activity dependent marker phosphorylated ribosomal protein S6 (p-rpS6), we mapped hetamine effects on the activity of cholinergic interneurons (ChIs) across the striatum. Amphetamine caused a delayed attenuation of ChI activity in all striatal subregions, and a dose-dependent effect in the ventral striatum/nucleus accumbens, a critical site of psychostimulant action.
Publisher: Elsevier BV
Date: 06-2020
Publisher: eLife Sciences Publications, Ltd
Date: 04-10-2017
Publisher: Elsevier BV
Date: 07-2013
Publisher: Elsevier BV
Date: 11-2020
Publisher: Cold Spring Harbor Laboratory
Date: 15-09-2022
DOI: 10.1101/2022.09.14.508004
Abstract: Multidisciplinary evidence suggests that instrumental performance is governed by two major forms of behavioural control: goal-directed and autonomous processes. Brain-state abnormalities affecting the striatum, such as ageing, often shift control towards autonomous—habit-like—behaviour, although the neural mechanisms responsible for this shift remain unknown. Here, combining instrumental conditioning with cell-specific functional mapping and manipulation in striatal neurons, we explored strategies that invigorate goal-directed action capacity in aged mice. In animals performing instrumental actions, D2- and D1-neurons of the aged striatum were engaged in a characteristically counterbalanced manner, something that related to the propensity to express autonomous behaviour. Long-lasting, cell-specific desensitisation of D2-neurons in aged transgenic mice recapitulated the uneven D2-to D1-neuron functional correspondence observed in young mice, an effect that enabled successful goal-directed action. Our findings contribute to the understanding of the neural bases of behavioural control and propose neural system interventions that enhance cognitive functioning in habit-prone brains.
Publisher: Public Library of Science (PLoS)
Date: 28-12-2012
Publisher: Cold Spring Harbor Laboratory
Date: 29-03-2022
DOI: 10.1101/2022.03.28.486040
Abstract: Performing several actions in swift succession is often necessary to exploit known contingencies in the environment. However, in order to remain successful when contingency rules change, streamlined action sequences must be adaptable. Here, by combining analyses of behavioural microstructure with circuit-specific manipulation in mice, we report on a relationship between action timing variability and successful adaptation that relies on post-synaptic targets of primary motor cortical (M1) projections to dorsolateral striatum (DLS). Using a two-lever instrumental task, we found that mice build successful action sequences by first establishing action scaffolds, from which they dynamically elongate as task requirements extend. Specific interruption of the M1→DLS circuit altered these dynamics, prompting actions that were less variable in their timing, overall reducing opportunities for success. Our results reveal a role for M1→DLS circuitry in setting the exploration/exploitation balance that is required for adaptively guiding the timing and success of instrumental action. Based on evidence from transsynaptic tracing experiments, we propose that such function may involve additional downstream subcortical processing relating to collateralisation of descending motor pathways to multiple basal ganglia centres.
Publisher: Elsevier BV
Date: 05-2023
Publisher: Elsevier BV
Date: 04-2016
DOI: 10.1016/J.NEURON.2016.03.006
Abstract: For goal-directed action to remain adaptive, new strategies are required to accommodate environmental changes, a process for which parafascicular thalamic modulation of cholinergic interneurons in the striatum (PF-to-CIN) appears critical. In the elderly, however, previously acquired experience frequently interferes with new learning, yet the source of this effect has remained unexplored. Here, combining sophisticated behavioral designs, cell-specific manipulation, and extensive neuronal imaging, we investigated the involvement of the PF-to-CIN pathway in this process. We found functional alterations of this circuit in aged mice that were consistent with their incapacity to update initial goal-directed learning, resulting in faulty activation of projection neurons in the striatum. Toxicogenetic ablation of CINs in young mice reproduced these behavioral and neuronal defects, suggesting that age-related deficits in PF-to-CIN function reduce the ability of older in iduals to resolve conflict between actions, likely contributing to impairments in adaptive goal-directed action and executive control in aging. VIDEO ABSTRACT.
Publisher: Springer Science and Business Media LLC
Date: 03-08-2011
DOI: 10.1038/NPP.2011.144
Publisher: Elsevier BV
Date: 06-2012
Publisher: Society for Neuroscience
Date: 28-05-2008
DOI: 10.1523/JNEUROSCI.1039-08.2008
Abstract: Psychostimulants and other drugs of abuse activate extracellular signal-regulated kinase (ERK) in the striatum, through combined stimulation of dopamine D 1 receptors (D1Rs) and glutamate NMDA receptors. Antipsychotic drugs activate similar signaling proteins in the striatum by blocking dopamine D 2 receptors (D2Rs). However, the neurons in which these pathways are activated by psychotropic drugs are not precisely identified. We used transgenic mice, in which enhanced green fluorescent protein (EGFP) expression was driven by D1R promoter ( drd1a -EGFP) or D2R promoter ( drd2 -EGFP). We confirmed the expression of drd1a -EGFP in striatonigral and drd2 -EGFP in striatopallidal neurons. Drd2 -EGFP was also expressed in cholinergic interneurons, whereas no expression of either promoter was detected in GABAergic interneurons. Acute cocaine treatment increased phosphorylation of ERK and its direct or indirect nuclear targets, mitogen- and stress-activated kinase-1 (MSK1) and histone H3, exclusively in D1R-expressing output neurons in the dorsal striatum and nucleus accumbens. Cocaine-induced expression of c-Fos and Zif268 predominated in D1R-expressing neurons but was also observed in D2R-expressing neurons. One week after repeated cocaine administration, cocaine-induced signaling responses were decreased, with the exception of enhanced ERK phosphorylation in dorsal striatum. The responses remained confined to D1R neurons. In contrast, acute haloperidol injection activated phosphorylation of ERK, MSK1, and H3 only in D2R neurons and induced c-fos and zif268 predominantly in these neurons. Our results demonstrate that cocaine and haloperidol specifically activate signaling pathways in two completely segregated populations of striatal output neurons, providing direct evidence for the selective mechanisms by which these drugs exert their long-term effects.
Publisher: Public Library of Science (PLoS)
Date: 10-03-2009
Publisher: Society for Neuroscience
Date: 22-01-2014
DOI: 10.1523/JNEUROSCI.4592-13.2014
Abstract: Decision-making depends on the ability to extract predictive information from the environment to guide future actions. Outcome-specific Pavlovian-instrumental transfer (PIT) provides an animal model of this process in which a stimulus predicting a particular outcome biases choice toward actions earning that outcome. Recent evidence suggests that cellular adaptations of δ-opioid receptors (DORs) on cholinergic interneurons (CINs) in the nucleus accumbens shell (NAc-S) are necessary for PIT. Here we found that modulation of DORs in CINs critically influences D 1 -receptor (D1R)-expressing projection neurons in the NAc-S to promote PIT. First, we assessed PIT-induced changes in signaling processes in dopamine D 1 - and D 2 -receptor-expressing neurons using drd2 -eGFP mice, and found that PIT-related signaling was restricted to non-D2R-eGFP-expressing neurons, suggesting major involvement of D1R-neurons. Next we confirmed the role of D1Rs pharmacologically: the D1R antagonist SCH-23390, but not the D2R antagonist raclopride, infused into the NAc-S abolished PIT in rats, an effect that depended on DOR activity. Moreover, asymmetrical infusion of SCH-23390 and the DOR antagonist naltrindole into the NAc-S also abolished PIT. DOR agonists were found to sensitize the firing responses of CINs in brain slices prepared immediately after the PIT test. We confirmed the opioid-acetylcholinergic influence over D1R-neurons by selectively blocking muscarinic M4 receptors in the NAc-S, which tightly regulate the activity of D1Rs, a treatment that rescued the deficit in PIT induced by naltrindole. We describe a model of NAc-S function in which DORs modulate CINs to influence both D1R-neurons and stimulus-guided choice between goal-directed actions.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 31-01-2020
Abstract: An intriguing characteristic of the striatum is the random spatial distribution and high degree of intermingling between expression of dopamine receptor types 1 (D1) and 2 (D2) within striatal projection neurons (SPNs). The resulting highly entropic mosaic extends through a homogeneous space and is mostly devoid of histological boundaries. The rules established locally by D1- and D2-expressing SPNs (D1-SPNs and D2-SPNs) are thus likely critical in defining how functional territories develop throughout the striatum. Matamales et al. found that activated D2-SPNs access and modify developing behavioral programs encoded by regionally defined ensembles of transcriptionally active D1-SPNs. This process is slow because it depends on the molecular integration of additive neuro-modulatory signals. However, with time, it creates the regional functional boundaries that are necessary to identify and shape specific learning in the striatum. Science , this issue p. 549
Publisher: Cold Spring Harbor Laboratory
Date: 26-09-2019
DOI: 10.1101/780346
Abstract: Extinction learning allows animals to withhold voluntary actions that are no longer related to reward and so provides a major source of behavioral control. Although such learning is thought to depend on dopamine signals in the striatum, the way the circuits mediating goal-directed control are reorganized during new learning remains unknown. Here, by mapping a dopamine-dependent transcriptional activation marker in large ensembles of striatal projection neurons (SPNs) expressing dopamine receptor type 1 (D1-SPNs) or 2 (D2-SPNs) in mice, we demonstrate an extensive and dynamic D2- to D1-SPN trans-modulation across the dorsal striatum that is necessary for updating previous goal-directed learning. Our findings suggest that D2-SPNs suppress the influence of outdated D1-SPN plasticity within functionally relevant striatal territories to reshape volitional action.
Publisher: eLife Sciences Publications, Ltd
Date: 23-10-2017
DOI: 10.7554/ELIFE.29908
Abstract: The acquisition of motor skills involves implementing action sequences that increase task efficiency while reducing cognitive loads. This learning capacity depends on specific cortico-basal ganglia circuits that are affected by normal ageing. Here, combining a series of novel behavioural tasks with extensive neuronal mapping and targeted cell manipulations in mice, we explored how ageing of cortico-basal ganglia networks alters the microstructure of action throughout sequence learning. We found that, after extended training, aged mice produced shorter actions and displayed squeezed automatic behaviours characterised by ultrafast oligomeric action chunks that correlated with deficient reorganisation of corticostriatal activity. Chemogenetic disruption of a striatal subcircuit in young mice reproduced age-related within-sequence features, and the introduction of an action-related feedback cue temporarily restored normal sequence structure in aged mice. Our results reveal static properties of aged cortico-basal ganglia networks that introduce temporal limits to action automaticity, something that can compromise procedural learning in ageing.
Publisher: Society for Neuroscience
Date: 09-10-2013
DOI: 10.1523/JNEUROSCI.1927-13.2013
Abstract: The ability of animals to extract predictive information from the environment to inform their future actions is a critical component of decision-making. This phenomenon is studied in the laboratory using the pavlovian–instrumental transfer protocol in which a stimulus predicting a specific pavlovian outcome biases choice toward those actions earning the predicted outcome. It is well established that this transfer effect is mediated by corticolimbic afferents on the nucleus accumbens shell (NAc-S), and recent evidence suggests that δ-opioid receptors (DORs) play an essential role in this effect. In DOR-eGFP knock-in mice, we show a persistent, learning-related plasticity in the translocation of DORs to the somatic plasma membrane of cholinergic interneurons (CINs) in the NAc-S during the encoding of the specific stimulus–outcome associations essential for pavlovian–instrumental transfer. We found that increased membrane DOR expression reflected both stimulus-based predictions of reward and the degree to which these stimuli biased choice during the pavlovian–instrumental transfer test. Furthermore, this plasticity altered the firing pattern of CINs increasing the variance of action potential activity, an effect that was exaggerated by DOR stimulation. The relationship between the induction of membrane DOR expression in CINs and both pavlovian conditioning and pavlovian–instrumental transfer provides a highly specific function for DOR-related modulation in the NAc-S, and it is consistent with an emerging role for striatal CIN activity in the processing of predictive information. Therefore, our results reveal evidence of a long-term, experience-dependent plasticity in opioid receptor expression on striatal modulatory interneurons critical for the cognitive control of action.
No related organisations have been discovered for Jay Bertran-Gonzalez.
Start Date: 2021
End Date: 12-2024
Amount: $912,402.00
Funder: Australian Research Council
View Funded ActivityStart Date: 09-2016
End Date: 09-2019
Amount: $375,000.00
Funder: Australian Research Council
View Funded ActivityStart Date: 2019
End Date: 12-2021
Amount: $464,678.00
Funder: Australian Research Council
View Funded ActivityStart Date: 12-2021
End Date: 12-2024
Amount: $378,205.00
Funder: Australian Research Council
View Funded Activity