Biology subjects

Kahnt, T.

Publications and source records attributed to Kahnt, T..

10 recordsLinked to original sources

bioRxiv2026

Reactivation during sleep segregates the neural representations of episodic memories

Sleep involves the reactivation of recently acquired memories, thereby shaping the neural representations supporting them. An essential feature of episodic memory (i.e., memory for events) is the link between specific elements (e.g., a cake) and the context in which they were embedded (e.g., a birthday party). We investigated how reactivation during sleep impacts item-context binding. Participants (N = 22) formed stories linking together objects in unique contexts. Using functional MRI, we measured the overlap between neural representations for contextually linked objects. During a 90-min nap, some object memories were reactivated by unobtrusively presenting object-specific sounds. Across multiple brain regions, reactivation reduced the overlap between representations of contextually linked memories, promoting object specificity. Furthermore, reactivation reduced the representational overlap between contexts, thereby promoting context specificity. Taken together, data suggest that reactivation during sleep decontextualizes memories. These results inform our understanding of how sleep contributes to interlinked memories embedded in naturalistic contexts and demonstrate that memory reactivation during sleep changes representations of memories within their distinctive contexts.

neuroscience↗

bioRxiv2026

Neurometabolic signatures of addiction vulnerability and heroin versus social seeking: a PET study in rats

Only a subset of heroin users develop addiction, characterized by binge-like heroin use and preference for heroin over other rewards, including social rewards. We recently established a rat model of these features. We trained rats to lever-press for social interaction and heroin (or saline, control) infusions and then tested heroin- and social-seeking and heroin-vs.-social choice. During 3-5 abstinence weeks, we used 2-deoxy-2-[{superscript 1}F]fluoro-D-glucose (FDG) PET imaging to assess regional brain metabolic activity at rest (homecage) and during heroin and social seeking. We assessed regional differences in FDG uptake using unbiased voxel-wise analysis and statistical parametric mapping, and correlated FDG uptake with principle-component-analysis-derived addiction severity score incorporating heroin intake, binge-like episodes, and heroin preference. Compared with saline-trained rats, heroin-trained rats showed overall higher FDG uptake across multiple brain regions at rest and during both reward-seeking tests. Comparison of heroin-vs.-social-seeking in heroin-trained rats showed higher uptake in claustrum/lateral striatum and auditory cortex during social seeking. Analysis of individual differences showed that addiction severity was primarily associated with metabolic alterations under resting conditions rather than during heroin- or social-seeking. At rest, higher addiction severity was associated with lower uptake in piriform cortex and higher uptake in ventral hippocampus, whereas during heroin-seeking, addiction severity was associated with lower uptake in post-subiculum and cerebellum. Addiction severity was not associated with differences in social seeking or FDG uptake during social seeking. These findings identify neurometabolic features of social and heroin seeking and heroin addiction vulnerability that can potentially serve as brain biomarkers and targets for neuromodulation. Significance StatementHeroin addiction develops in only a subset of users, yet the determinants of vulnerability versus resilience to addiction remain largely unknown. We combined a rat model capturing key features of heroin addiction, including binge-like heroin intake and preference for heroin over social interaction, with behavioral heroin- and social-seeking assays and longitudinal whole-brain metabolic imaging using FDG-PET. We identified distinct patterns of neurometabolic alterations associated with heroin self-administration and addiction severity at rest and in the context of heroin seeking. In contrast, heroin self-administration and addiction severity were not significantly associated with neurometabolic alterations during social seeking. These findings highlight brain-wide neurometabolic features of vulnerability to heroin addiction that can serve as brain biomarkers and targets for neuromodulation.

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bioRxiv2025

Distinct contributions of anterior and posterior orbitofrontal cortex to outcome-guided behavior

The lateral orbitofrontal cortex (OFC) is critical for flexibly adjusting choices when outcome values change. Anterior and posterior parts of the human lateral OFC differ in cytoarchitecture and connectivity, but whether these subregions make differential contributions to outcome-guided (i.e., goal-directed) behavior remains unclear. Outcome-guided behavior requires (a) representations of stimulus-outcome associations and (b) inferring the current value of options when making decisions. Here, we test whether these two functions are differentially supported by the posterior (pOFC) and anterior (aOFC) parts of the lateral OFC, using transcranial magnetic stimulation (TMS) to selectively disrupt activity in functional networks centered on the pOFC and aOFC during a two-day outcome devaluation task. Participants (n = 48) received pOFC or aOFC network-targeted TMS either on day 1 before learning associations between visual stimuli and sweet or savory food odors, or on day 2 before a meal that selectively devalued one of these outcomes, followed by a choice test. TMS targeting pOFC, but not aOFC, before the meal on day 2 disrupted outcome-guided behavior, as measured by choices of stimuli predicting non-sated rewards in the post-meal choice test. In contrast, TMS targeting aOFC, but not pOFC, before learning on day 1 similarly impaired behavior in the post-meal choice test on day 2. These findings demonstrate that anterior and posterior parts of the lateral OFC make distinct contributions to outcome-guided behavior by supporting learning of stimulus-outcome associations and inferring the current value of options, respectively.

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bioRxiv2024

Dopaminergic responses to identity prediction errors depend differently on the orbitofrontal cortex and hippocampus

Adaptive behavior depends on the ability to predict specific events, particularly those related to rewards. Armed with such associative information, we can infer the current value of predicted rewards based on changing circumstances and desires. To support this ability, neural systems must represent both the value and identity of predicted rewards, and these representations must be updated when they change. Here we tested whether prediction error signaling of dopamine neurons depends on two areas known to represent the specifics of rewarding events, the HC and OFC. We monitored the spiking activity of dopamine neurons in rat VTA during changes in the number or flavor of expected rewards designed to induce errors in the prediction of reward value or reward identity, respectively. In control animals, dopamine neurons registered both error types, transiently increasing firing to additional drops of reward or changes in reward flavor. These canonical firing signatures of value and identity prediction errors were significantly disrupted in rats with ipsilateral neurotoxic lesions of either HC or OFC. Specifically, HC lesions caused a failure to register either type of prediction error, whereas OFC lesions caused persistent signaling of identity prediction errors and much more subtle effects on signaling of value errors. These results demonstrate that HC and OFC contribute distinct types of information to the computation of prediction errors signaled by dopaminergic neurons.

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bioRxiv2023

Expectancy-related changes in firing of dopamine neurons depend on hippocampus

The orbitofrontal cortex (OFC) and hippocampus (HC) are both implicated in forming the cognitive or task maps that support flexible behavior. Previously, we used the dopamine neurons as a sensor or tool to measure the functional effects of OFC lesions (Takahashi et al., 2011). We recorded midbrain dopamine neurons as rats performed an odor-based choice task, in which errors in the prediction of reward were induced by manipulating the number or timing of the expected rewards across blocks of trials. We found that OFC lesions ipsilateral to the recording electrodes caused prediction errors to be degraded consistent with a loss in the resolution of the task states, particularly under conditions where hidden information was critical to sharpening the predictions. Here we have repeated this experiment, along with computational modeling of the results, in rats with ipsilateral HC lesions. The results show HC also shapes the map of our task, however unlike OFC, which provides information local to the trial, the HC appears to be necessary for estimating the upper-level hidden states based on the information that is discontinuous or separated by longer timescales. The results contrast the respective roles of the OFC and HC in cognitive mapping and add to evidence that the dopamine neurons access a rich information set from distributed regions regarding the predictive structure of the environment, potentially enabling this powerful teaching signal to support complex learning and behavior.

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bioRxiv2021

Opioid antagonism reduces wanting by strengthening frontostriatal connectivity

Goal-directed behavior depends on both motivational ("wanting") and hedonic ("liking") dimensions of rewards. Previous animal and human research linked wanting and liking to anatomically and neurochemically distinct brain mechanisms, but it remains unknown as to how the different brain regions and neurotransmitter systems interact in processing distinct reward dimensions. Here, we assessed how pharmacological manipulations of opioid and dopamine receptor activation modulate the neural processing of wanting and liking in humans in a randomized, placebo-controlled, double-blind clinical trial. Blocking opioid receptor activation with naltrexone selectively reduced wanting of rewards, which on a neural level was reflected by stronger coupling between dorsolateral prefrontal cortex and the striatum under naltrexone compared with placebo. Our findings thus provide insights into how opioid receptors mediate frontostriatal gating of specifically motivational, not hedonic, aspects of rewards.

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bioRxiv2020

Enhanced reinstatement of naturalistic event memories due to hippocampal-network-targeted stimulation

Episodic memory involves the reinstatement of distributed patterns of brain activity present when events were initially experienced. The hippocampus is thought to coordinate reinstatement via its interactions with a network of brain regions, but this hypothesis has not been causally tested in humans. The current study directly tested the involvement of the hippocampal network in reinstatement using network-targeted noninvasive stimulation. We measured reinstatement of multi-voxel patterns of fMRI activity during encoding and retrieval of naturalistic video clips depicting everyday activities. Reinstatement of video-specific activity patterns was robust in posterior-parietal and occipital areas previously implicated in event reinstatement. Theta-burst stimulation targeting the hippocampal network increased videospecific reinstatement of fMRI activity patterns in occipital cortex and improved memory accuracy relative to stimulation of a control out-of-network location. Furthermore, stimulation targeting the hippocampal network influenced the trial-by-trial relationship between hippocampal activity during encoding and later reinstatement in occipital cortex. These findings implicate the hippocampal network in the reinstatement of spatially distributed patterns of event-specific activity, and identify a role for the hippocampus in encoding complex naturalistic events that later undergo cortical reinstatement.

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bioRxiv2020

Human orbitofrontal cortex is necessary for behavior based on inferred, not experienced outcomes

When direct experience is unavailable, animals and humans can imagine or infer the future to guide decisions. Behavior based on direct experience versus inference may recruit distinct but overlapping brain circuits. In rodents, the orbitofrontal cortex (OFC) contains neural signatures of inferred outcomes, and OFC is necessary for behavior that requires inference but not for responding driven by direct experience. In humans, OFC activity is also correlated with inferred outcomes, but it is unclear whether OFC activity is required for inference-based behavior. To test this, we used non-invasive network-based continuous theta burst stimulation (cTBS) to target lateral OFC networks in the context of a sensory preconditioning task that was designed to isolate inference-based behavior from responding that can be based on direct experience alone. We show that relative to sham, cTBS targeting this network impairs reward-related behavior in conditions in which outcome expectations have to be mentally inferred. In contrast, OFC-targeted stimulation does not impair behavior that can be based on previously experienced stimulus-outcome associations. These findings suggest that activity in the targeted OFC network supports decision making when outcomes have to be mentally simulated, providing converging cross-species evidence for a critical role of OFC in model-based but not model-free control of behavior.

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bioRxiv2019

Targeted stimulation of human orbitofrontal networks disrupts outcome-guided behavior

Outcome-guided behavior requires knowledge about the current value of expected outcomes. Such behavior can be isolated in the reinforcer devaluation task, which assesses the ability to infer the current value of rewards after devaluation. Animal lesion studies demonstrate that orbitofrontal cortex (OFC) is necessary for normal behavior in this task, but a causal role for human OFC in outcome-guided behavior has not been established. Here we used sham-controlled non-invasive continuous theta-burst stimulation (cTBS) to temporarily disrupt human OFC network activity prior to devaluation of food odor rewards in a between-subjects design. Subjects in the sham group appropriately avoided Pavlovian cues associated with devalued food odors. However, subjects in the stimulation group persistently chose those cues, even though devaluation of food odors themselves was unaffected by cTBS. This behavioral impairment was mirrored in changes in resting-stated functional magnetic resonance imaging (rs-fMRI) activity, such that subjects in the stimulation group exhibited reduced global OFC network connectivity after cTBS, and the magnitude of this reduction was correlated with choices after devaluation. These findings demonstrate the feasibility of indirectly targeting the human OFC with non-invasive cTBS, and indicate that OFC is specifically required for inferring the value of expected outcomes.

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bioRxiv2019

Dopamine neuron ensembles signal the content of sensory prediction errors

Dopamine neurons respond to errors in predicting value-neutral sensory information. These data, combined with causal evidence that dopamine transients support sensory-based associative learning, suggest that the dopamine system signals a multidimensional prediction error. Yet such complexity is not evident in individual neuron or average neural activity. How then do downstream areas know what to learn in response to these signals? One possibility is that information about content is contained in the pattern of firing across many dopamine neurons. Consistent with this, here we show that the pattern of firing across a small group of dopamine neurons recorded in rats signals the identity of a mis-predicted sensory event. Further, this same information is reflected in the BOLD response elicited by sensory prediction errors in human midbrain. These data provide evidence that ensembles of dopamine neurons provide highly specific teaching signals, opening new possibilities for how this system might contribute to learning.

neuroscience↗