A non-Hebbian code for episodic memory Hebbian plasticity has long dominated neurobiological models of memory formation. Yet, plasticity rules operating on one-shot episodic memory timescales rarely depend on both pre- and postsynaptic spiking, challenging Hebbian theory in this crucial regime. Here, we present an episodic memory model governed by a simpler rule depending only on presynaptic activity. We show that this rule, capitalizing on high-dimensional neural activity with restricted transitions, naturally stores episodes as paths through complex state spaces like those underlying a world model. The resulting memory traces, which we term path vectors, are highly expressive and decodable with an odor-tracking algorithm. We show that path vectors are robust alternatives to Hebbian traces, support one-shot sequential and associative recall, along with policy learning, and shed light on specific hippocampal plasticity rules. Thus, non-Hebbian plasticity is sufficient for flexible memory and learning and well-suited to encode episodes and policies as paths through a world model.
Neglect symptoms are related to a prediction-hypersensitivity in ipsilesional space The precise cognitive mechanisms underlying spatial neglect are not fully understood. Recent studies have provided the first evidence for aberrant behavioral and electrophysiological prediction and prediction error responses in patients with neglect, but also in right-hemispheric (RH) stroke patients without neglect. For prediction-dependent attention, as assessed with Posner-type cueing paradigms with volatile cue-target contingencies, studies in healthy volunteers point to a crucial role of the right temporo-parietal junction (rTPJ) – as part of a network commonly disrupted in neglect. In order to study altered prediction-dependent attention in patients with RH damage and neglect, the present study employed a spatial cueing paradigm with unsignalled changes in the cue’s predictive value in 26 RH patients, 21 left-hemispheric (LH) patients, and 33 healthy elderly controls. The inference of the changing cue’s predictive value was assessed with a Rescorla-Wagner learning model of response times (RTs) and participants’ ratings. We tested for lesion-side-dependent relationships between the computational model parameters, ratings, and neuropsychological performance. Moreover, we investigated links between the behavioral signatures of predictive processing and lesion anatomy (lesion location and disconnection). The results provided no evidence for a predictive inference deficit, but revealed a correlation between a hypersensitivity of RTs to inferred predictions for ipsilesional stimuli and neglect symptoms in RH patients. Irrespective of symptoms of neglect, the rating of the cue’s predictive value deviated more from the actual values in RH patients. RT hypersensitivity for ipsilesional targets was linked to disconnection within fronto-parietal, fronto-occipital, and temporo-parietal pathways. These findings provide novel insights into the role of altered prediction-dependent processing for neglect as assessed by different read-outs, highlighting an exaggerated response adaption to predictions of ipsilesional stimuli.
Cortico-striatal action control inherent of opponent cognitive-motivational styles Turning on cue or stopping at a red light requires attending to such cues to select action sequences, or suppress action, in accordance with learned cue-associated action rules. Cortico-striatal projections are an essential part of the brain’s attention–motor interface. Glutamate-sensing microelectrode arrays were used to measure glutamate transients in the dorsomedial striatum (DMS) of male and female rats walking a treadmill and executing cued turns and stops. Prelimbic–DMS projections were chemogenetically inhibited to determine their behavioral necessity and the cortico-striatal origin of cue-evoked glutamate transients. Furthermore, we investigated rats exhibiting preferably goal-directed (goal trackers, GTs) versus cue-driven attention (sign-trackers, STs), to determine the impact of such cognitive-motivational biases on cortico-striatal control. GTs executed more cued turns and initiated such turns more slowly than STs. During turns, but not missed turns or cued stops, cue-evoked glutamate concentrations were higher in GTs than in STs. In STs, turn cue-locked glutamate concentrations frequently peaked twice or three times, contrasting with predominately single peaks in GTs. In GTs, but not STs, inhibition of prelimbic–DMS projections attenuated turn rates and turn cue-evoked glutamate concentrations and increased the number of turn cue-locked glutamate peaks. These findings indicate that turn cue-evoked glutamate release in GTs is tightly controlled by cortico-striatal neuronal activity. In contrast, in STs, glutamate release from DMS glutamatergic terminals may be regulated by other striatal circuitry, preferably mediating cued suppression of action and reward tracking. As cortico-striatal dysfunction has been hypothesized to contribute to a wide range of disorders, including complex movement control deficits in Parkinson’s disease and compulsive drug taking, the demonstration of phenotypic contrasts in cortico-striatal control implies the presence of individual vulnerabilities for such disorders.
The Modulation by the Locus Coeruleus of Recent and Remote Memory Retrieval is Activity-Dependent The hippocampus plays a crucial role in acquiring, storing, and retrieving associative experience. Whereas neuromodulatory control of the hippocampus by the locus coeruleus (LC) enhances memory acquisition and consolidation, less is known about its influence on memory retrieval. The LC fires at tonic (0.5–8 Hz) and phasic frequencies (10–25 Hz), relative to arousal and affective states. Here, we explored to what extent LC stimulation at different frequencies (2–100 Hz) and respective stimulation patterns, before retrieval of recently acquired or remote spatial memory, alter working memory (WM) or reference memory (RM) in male rats. Here, animals learned a spatial memory task in an eight-arm radial maze over a period of 15 days. LC stimulation before recent memory testing did not affect WM. However, LC stimulation at 20 or 100 Hz, but not 5–10 Hz, impaired retrieval of recently consolidated RM. These frequency-dependent impairments were abolished by intracerebral β-adrenergic receptor (β-AR), but not D1/D5 receptor, antagonism. When memory retrieval was assessed 4 weeks after initial consolidation (Day 34), RM was significantly impaired compared to the final day of recent memory testing (on Day 6). RM was not altered by LC stimulation before remote memory retrieval. However, LC stimulation at 2–100 Hz improved WM. Taken together, these data suggest that frequency-dependent NA release from the LC disrupts retrieval of recently acquired RM via activation of β-AR. Strikingly, increasing LC activity in general improves WM of a remotely acquired spatial learning task, assessed 4 weeks after the recent memory testing, suggesting that the increased effort of sustaining WM of a task learned in the past requires higher LC engagement.
Visual hallucinations in Parkinson’s disease: spotlight on central cholinergic dysfunction Visual hallucinations are a common non-motor feature of Parkinson’s disease and have been associated with accelerated cognitive decline, increased mortality and early institutionalization. Despite their prevalence and negative impact on patient outcomes, the repertoire of treatments aimed at addressing this troubling symptom is limited. Over the past two decades, significant contributions have been made in uncovering the pathological and functional mechanisms of visual hallucinations, bringing us closer to the development of a comprehensive neurobiological framework.
Convergent evidence now suggests that degeneration within the central cholinergic system may play a significant role in the genesis and progression of visual hallucinations. Here, we outline how cholinergic dysfunction may serve as a potential unifying neurobiological substrate underlying the multifactorial and dynamic nature of visual hallucinations.
Drawing upon previous theoretical models, we explore the impact that alterations in cholinergic neurotransmission has on the core cognitive processes pertinent to abnormal perceptual experiences. We conclude by highlighting that a deeper understanding of cholinergic neurobiology and individual pathophysiology may help to improve established and emerging treatment strategies for the management of visual hallucinations and psychotic symptoms in Parkinson’s disease.
Cognitive reserve types and depressive symptoms development in late-life: a population-based cohort study Cognitive reserve (CR) describes individual differences in susceptibility to brain damage that translates into varying dementia onsets and may also influence the occurrence of depressive symptoms. Within a population-based cohort of older people, we investigated two operationalizations of CR, residual- and activity-based approaches, in their association with the development of depressive symptoms.
The role of striatum in controlling waiting during reactive and self-timed behaviors The ability to wait before responding is crucial for many cognitive functions, including reaction time tasks, where one must resist premature actions before the stimulus and respond quickly once the stimulus is presented. However, the brain regions governing waiting remain unclear. Using localized excitotoxic lesions, we investigated the roles of the motor cortex (MO) and sensorimotor dorsolateral striatum (DLS) in male rats performing a conditioned lever release task with variable delays. Neural activity in both MO and DLS showed similar firing patterns during waiting and responding periods. However, only bilateral DLS lesions caused a sustained increase in premature (anticipatory) responses, whereas bilateral MO lesions primarily prolonged reaction times. In a self-timing version of the task, where rats held a lever for a fixed delay before release, DLS lesions caused a leftward shift in response timing, leading to persistently greater premature responses. These waiting deficits were accompanied by reduced motor vigor, such as slower reward-orienting locomotion. Our findings underscore the critical role of the sensorimotor striatum in regulating waiting behavior in timing-related behaviors.
Striatal dopamine D2/D3 receptor regulation of human reward processing and behaviour Signalling at dopamine D2/D3 receptors is thought to underlie motivated behaviour, pleasure experiences and emotional expression based on animal studies, but it is unclear if this is the case in humans or how this relates to neural processing of reward stimuli. Using a randomised, double-blind, placebo-controlled, crossover neuroimaging study, we show in healthy humans that sustained dopamine D2/D3 receptor antagonism for 7 days results in negative symptoms (impairments in motivated behaviour, hedonic experience, verbal and emotional expression) and that this is related to blunted striatal response to reward stimuli. In contrast, 7 days of partial D2/D3 agonism does not disrupt reward signalling, motivated behaviour or hedonic experience. Both D2/D3 antagonism and partial agonism induce motor impairments, which are not related to striatal reward response. These findings identify a central role for D2/D3 signalling and reward processing in the mechanism underlying motivated behaviour and emotional responses in humans, with implications for understanding neuropsychiatric disorders such as schizophrenia and Parkinson’s disease.