bioRxiv Subject Collection: Neuroscience's Journal
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Saturday, May 4th, 2024
| Time |
Event |
| 2:18a |
Does age protect against loss of tonotopy after acute deafness in adulthood?
The mammalian auditory system develops a topographical organization of sound frequencies along its pathways, also called tonotopy, as a result of early auditory input. In contrast, sensory deprivation during early development results in no or only rudimentary tonotopic organization. This study addresses two questions: 1) How robust is the tonotopy when hearing fails in adulthood? 2) What role does age play at time of deafness? To address these questions, we deafened young and old adult rats with normal hearing. One month after deafness, both groups were unilaterally supplied with cochlear implants and electrically stimulated for two hours. The central auditory neurons, which were activated as a result of the local electrical intracochlear stimulation, were visualized using Fos staining. While the auditory system of young rats lost the tonotopic organization throughout the brainstem, the auditory system of the older rats mainly sustained its tonotopy. It can be proposed that neuronal plasticity prevails in the central auditory system of young adult rats, while neuronal stability prevails in the brains of aging rats. Consequently, age may be an important factor in protecting a hearing-experienced adult auditory system from a rapid loss of tonotopy when suffering from acute hearing loss. Furthermore, the study provides compelling evidence that acute deafness in young adult patients should be diagnosed as early as possible to prevent maladaptation of the central auditory system and thus achieve the optimal hearing outcome with a hearing prosthesis. | | 2:18a |
Two routes to value-based decisions in Parkinsons disease: differentiating incremental reinforcement learning from episodic memory
Patients with Parkinsons disease are impaired at incremental reward-based learning. It is typically assumed that this impairment reflects a loss of striatal dopamine. However, many open questions remain about the nature of reward-based learning deficits in Parkinsons. Recent studies have found that a combination of different cognitive and computational strategies contribute even to simple reward-based learning tasks, suggesting a possible role for episodic memory. These findings raise critical questions about how incremental learning and episodic memory interact to support learning from past experience and what their relative contributions are to impaired decision-making in Parkinsons disease. Here we addressed these questions by asking patients with Parkinsons disease (n=26) both on and off their dopamine replacement medication and age- and education-matched healthy controls (n=26) to complete a task designed to isolate the contributions of incremental learning and episodic memory to reward-based learning and decision-making. We found that Parkinsons patients performed as well as healthy controls when using episodic memory, but were impaired at incremental reward-based learning. Dopamine replacement medication remediated this deficit while enhancing subsequent episodic memory for the value of motivationally relevant stimuli. These results demonstrate that Parkinsons patients are impaired at learning about reward from trial-and-error when episodic memory is properly controlled for, and that learning based on the value of single experiences remains intact in patients with Parkinsons disease. | | 4:37a |
Dark exposure reduces high-frequency hearing loss in C57BL/6J mice
Plastic changes in the brain are primarily limited to early postnatal periods. Recovery of adult brain plasticity is critical for the effective development of therapies. A brief (1-2 week) duration of visual deprivation (dark exposure, DE) in adult mice can trigger functional plasticity of thalamocortical and intracortical circuits in the primary auditory cortex suggesting improved sound processing. We tested if DE enhances the ability of adult mice to detect sounds. We trained and continuously evaluated the behavioral performance of mice in control and DE conditions using automated home-cage training. Consistent with age-related peripheral hearing loss present in C57BL/6J mice, we observed decreased performance for high-frequency sounds with age, which was reduced by DE. In CBA mice with preserved peripheral hearing, we also found that DE enhanced auditory performance in low and mid frequencies over time compared to the control. | | 12:17p |
Dopamine and acetylcholine correlations in the nucleus accumbens depend on behavioral task states
Dopamine in the nucleus accumbens ramps up as animals approach desired goals. These ramps have received intense scrutiny because they seem to violate long-held hypotheses on dopamine function. Furthermore, it has been proposed that they are driven by local acetylcholine release, i.e., that they are mechanistically separate from dopamine signals related to reward prediction errors. Here, we tested this hypothesis by simultaneously recording accumbal dopamine and acetylcholine signals in rats executing a task involving motivated approach. Contrary to recent reports, we found that dopamine ramps were not coincidental with changes in acetylcholine. Instead, we found that acetylcholine could be positively, negatively, or uncorrelated with dopamine depending on whether the task phase was determined by a salient cue, reward prediction error, or active approach, respectively. Our results suggest that accumbal dopamine and acetylcholine are largely independent but may combine to engage different postsynaptic mechanisms depending on the behavioral task states. | | 12:17p |
Modulation of aggression by social novelty recognition memory in the hippocampal CA2 region
The dorsal CA2 subregion (dCA2) of the hippocampus exerts a critical role in social novelty recognition (SNR) memory and in the promotion of social aggression. Whether the social aggression and SNR memory functions of dCA2 are related or represent independent processes is unknown. Here we investigated the hypotheses that an animal is more likely to attack a novel compared to familiar animal and that dCA2 promotes social aggression through its ability to discriminate between novel and familiar conspecifics. To test these ideas, we conducted a multi-day resident intruder (R-I) test of aggression towards novel and familiar conspecifics. We found that mice were more likely to attack a novel compared to familiarized intruder and that silencing of dCA2 caused a more profound inhibition of aggression towards a novel than familiarized intruder. To explore whether and how dCA2 pyramidal neurons encode aggression, we recorded their activity using microendoscopic calcium imaging throughout the days of the R-I test. We found that a fraction of dCA2 neurons were selectively activated or inhibited during exploration, dominance, and attack behaviors and that these signals were enhanced during interaction with a novel compared to familiarized conspecific. Based on dCA2 population activity, a set of binary linear classifiers accurately decoded whether an animal was engaged in each of these forms of social behavior. Of particular interest, the accuracy of decoding aggression was greater with novel compared to familiarized intruders, with significant cross-day decoding using the same familiar animal on each day but not for a familiar-novel pair. Together, these findings demonstrate that dCA2 integrates information about social novelty with signals of behavioral state to promote aggression towards novel conspecifics. | | 12:17p |
Sexually dimorphic phenotypes and the role of androgen receptors in UBE3A-dependent autism spectrum disorder
Autism spectrum disorders (ASDs) are characterized by social, communication, and behavioral challenges. UBE3A is one of the most common ASD genes. ASDs display a remarkable sex difference with a 4:1 male to female prevalence ratio; however, the underlying mechanism remains largely unknown. Using the UBE3A-overexpressing mouse model for ASD, we studied sex differences at behavioral, genetic, and molecular levels. We found that male mice with extra copies of Ube3A exhibited greater impairments in social interaction, repetitive self-grooming behavior, memory, and pain sensitivity, whereas female mice with UBE3A overexpression displayed greater olfactory defects. Social communication was impaired in both sexes, with males making more calls and females preferring complex syllables. At the molecular level, androgen receptor (AR) levels were reduced in both sexes due to enhanced degradation mediated by UBE3A. However, AR reduction significantly dysregulated AR target genes only in male, not female, UBE3A-overexpressing mice. Importantly, restoring AR levels in the brain effectively normalized the expression of AR target genes, and rescued the deficits in social preference, grooming behavior, and memory in male UBE3A-overexpressing mice, without affecting females. These findings suggest that AR and its signaling cascade play an essential role in mediating the sexually dimorphic changes in UBE3A-dependent ASD. | | 12:17p |
Dorsal prefrontal cortex drives perseverative behavior in mice
Perseveration -- repeating one choice when others would generate larger rewards -- is a common behavior, but neither its purpose nor neuronal mechanisms are understood. Here we demonstrate a neural correlate and causal role of dorsal prefrontal cortex (area MOs) in perseveration in mice performing a dynamic reward learning task. An auditory go cue signaled mice to turn a wheel either left or right, with the reward probability of each action switching in blocks. Mice perseverated, gaining suboptimal reward, but were faster when making repeated choices. Neuropixels recordings found neurons whose activity correlated with perseveration and predicted rapid reaction times, almost exclusively in MOs. Optogenetically inhibiting MOs reduced perseveration and slowed reaction times. In contrast, inactivating medial prefrontal cortex at choice time did not have any effect but impaired learning if delivered after reward delivery. In this task, therefore, MOs encodes a perseverative decision variable, and is necessary for mediating the effect of this decision variable on choice and reaction time. | | 12:17p |
Protective role of parenthood on age-related brain function in mid- to late-life
The experience of parenthood can profoundly alter ones body, mind, and environment, yet we know little about the long-term associations between parenthood and brain function and aging in adulthood. Here, we investigate the link between number of children parented (parity) and age on brain function in 19,964 females and 17,607 males from the UK Biobank. In both females and males, increased parity was positively associated with functional connectivity, particularly within the somato/motor network. Critically, the spatial topography of parity-linked effects was inversely correlated with the impact of age on functional connectivity across the brain for both females and males, suggesting that a higher number of children is associated with patterns of brain function in the opposite direction to age-related alterations. These results indicate that the changes accompanying parenthood may confer benefits to brain health across the lifespan, highlighting the importance of future work to understand the associated mechanisms. | | 12:17p |
Acetylcholine demixes heterogeneous dopamine signals for learning and moving
Midbrain dopamine neurons promote reinforcement learning and movement vigor. A major outstanding question is how dopamine-recipient neurons in the striatum parse these heterogeneous signals. Here we characterized dopamine and acetylcholine release in the dorsomedial striatum (DMS) of rats perform- ing a decision-making task. We found that dopamine acted as a reward prediction error (RPE), modulating behavior and DMS spiking on subsequent trials when coincident with pauses in cholinergic release. In contrast, at task events that elicited coincident bursts of acetylcholine and dopamine, dopamine preceded contralateral movements and predicted movement vigor without inducing plastic changes in DMS firing rates. Our findings provide a circuit-level mechanism by which cholinergic modulation allows the same dopamine signals to be used for either movement or learning depending on instantaneous behavioral context. | | 12:17p |
A neurometabolic mechanism for effort-based decision-making in the dmPFC/dACC
Motivation levels vary across individuals, yet the underlying mechanisms driving these differences remain elusive. The dorsomedial prefrontal cortex/dorsal anterior cingulate cortex (dmPFC/dACC) and the anterior insula (aIns) play crucial roles in effort-based decision-making. Here, we investigate the influence of lactate, a key metabolite indicating energy deficit, on decisions involving both physical and mental effort, as well as its effects on neural activation. Using proton magnetic resonance spectroscopy and functional MRI in 75 participants, we find that higher lactate levels in the dmPFC/dACC are associated with reduced motivation for physical effort, a relationship mediated by neural activity within this region. Additionally, plasma and dmPFC/dACC lactate levels correlate, suggesting a systemic influence on brain metabolism. Supported by path analysis, our results highlight lactate's role as a modulator of dmPFC/dACC activity, hinting at a neurometabolic mechanism that integrates both peripheral and central metabolic states with brain function in effort-based decision-making. | | 11:16p |
A gentle palette of plasma membrane dyes
Plasma membrane stains are one of the most important organelle markers for unambiguous assignments of individual cells and monitoring membrane morphology and dynamics. The state-of-the-art PM stains are bright, specific, fluorogenic, and compatible with super-resolution imaging. However, when recording membrane dynamics, particularly under light-intensive microscopes, PM is prone to photodynamic damages due to its phospholipid bilayer nature. Here we developed PK Mem dyes tailored for time-lapse fluorescence imaging. By integrating triplet-state quenchers into the MemBright dyes featuring cyanine chromophores and amphiphilic zwitterion anchors, PK Mem dyes exhibited a three-fold reduction in phototoxicity and a more than four-fold improvement in photostability in imaging experiments. These dyes enable 2D and 3D imaging of live or fixed cancer cell lines and a wide range of primary cells, at the same time pair well with various fluorescent markers. PK Mem dyes can be applied to neuronal imaging in brain slices and in vivo two-photon imaging. The gentle nature of PK Mem palette enables ultralong-term recording of cell migration and cardiomyocyte beating. Notably, PK Mem dyes are optically compatible with STED/SIM imaging, which can handily upgrade the routine of time-lapse neuronal imaging, such as growth cone tracking and mitochondrial transportations, into nanoscopic resolutions. |
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