key: cord-0276778-akypki92
authors: Koch, Christoph; Bäuchl, Christian; Glöckner, Franka; Riedel, Philipp; Petzold, Johannes; Smolka, Michael; Li, Shu-Chen; Schuck, Nicolas W.
title: L-DOPA enhances hippocampal direction signals in younger and older adults
date: 2021-08-19
journal: bioRxiv
DOI: 10.1101/2021.08.18.456677
sha: b3a68c6be1da0046d347bddf66286bafa295988c
doc_id: 276778
cord_uid: akypki92

Previous studies indicate a role of dopamine in hippocampus-dependent spatial navigation. Although neural representations of direction are an important aspect of spatial cognition, it is not well understood whether dopamine directly affects these representations, or only impacts other aspects of spatial brain function. Moreover, both dopamine and spatial cognition decline sharply during age, raising the question which effect dopamine has on directional signals in the brain of older adults. To investigate these questions, we used a double-blind cross-over L-DOPA/Placebo intervention design in which 43 younger and 37 older adults navigated in a virtual spatial environment while undergoing functional magnetic resonance imaging (fMRI). We studied the effect of L-DOPA, a DA precursor, on fMRI activation patterns that encode spatial walking directions that have previously been shown to lose specificity with age. This was done in predefined regions of interest, including the early visual cortex, retrosplenial cortex, and hippocampus. Classification of brain activation patterns associated with different walking directions was improved in the hippocampus and the retrosplenial cortex following L-DOPA administration. This suggests that DA enhances the specificity of neural representations of walking direction in these areas. In the hippocampus these results were found in both age groups, while in the RSC they were only observed in younger adults. Taken together, our study provides evidence for a mechanistic link between DA and the specificity of neural responses during spatial navigation. Significance Statement The sense of direction is an important aspect of spatial navigation, and neural representations of direction can be found throughout a large network of space-related brain regions. But what influences how well these representations track someone’s true direction? Using a double-blind cross-over L-DOPA/Placebo intervention design, we find causal evidence that the neurotransmitter dopamine impacts the fidelity of direction selective neural representations in the human hippocampus and retrosplenial cortex. Interestingly, the effect of L-DOPA was either equally present or even smaller in older adults, despite the well-known age related decline of dopamine. These results provide novel insights into how dopamine shapes the neural representations that underlie spatial navigation.

the location of five different objects, but the trial structure and procedures were identical 147 otherwise. Completing one session took participants between 14 and 49 minutes.

Cue Placement Feedback Cue 2s 4s max. 60s time Figure 1 : Task procedure during feedback phase. Each trial started with a fixation cross on a grey background for two seconds. Afterwards a cue was presented showing the object to which participants needed to navigate (object locations were learned during encoding phase). The participant then had 60 seconds to navigate from their starting location (cross) to the object location according to their spatial memory. Participants indicated that they had arrived at the remembered location (circle) by pressing a response button, after which the object appeared at its true location. Participants could observe the difference between their response and the correct location and were required to navigate towards and walk over the correct location, before the cue of the next trial was presented.

Following a double-blind drug administration design, participants were given either a total given about 10 minutes before subjects entered the MRI scanner, roughly one hour before 154 the spatial navigation task began. To assure high dopamine availability during the task, 155 a second booster dosage (75mg L-DOPA/Placebo) was administered roughly ten minutes Each ROI was created from anatomical labels obtained from Mindboggle's FreeSurfer-based 182 segmentation of each participant's individual T1-weighted images (Klein et al., 2017 Because session was associated with intervention type (placebo or L-DOPA), we also 313 adopted a within-session approach for corss-validation. Specifically, cross-session cross-314 validation was problematic in two ways: First, it could not be used to asses intervention 315 effects that may differ between sessions. Second, training on data from a DA session and 316 testing on a Placebo session (and vice versa) would risk that DA induced changes in direction 317 specific activation patterns could result in reduced classification. To address these issues, 318 data from one session was separated into three folds, and cross-validated decoding was per-319 formed across these folds from the same session. An equal number of events per direction in 320 each fold was ensured as above. The separation into odd and even events was dropped due 

where x denotes the angular difference and τ the precision (the inverse of the variance, 1 σ 2 ). Such a model is given by

where a denotes the classification accuracy. Models were fitted separately within each par- 

Investigating the predicted probabilities by the logistic regression directly, rather than the 443 percent of correctly predicted events, revealed a peak at the true direction and decreasing 444 probabilities for the off-target directions in RSC and EVC, as expected (see Fig. 3B .).

Notably, in this more sensitive analysis also the HC exhibited an above-chance probability 446 of the target direction (t(83) = 5.346, p < .001, corr.).

Older adults Fig. 4A .

In addition, we also found a main effect of age group (χ 2 (1) = 6.273, p = .012) and a 461 age group × ROI interaction (χ 2 (4) = 60.970, p < .001). We will elucidate these age effects Finally, we asked whether task performance (spatial distance error) was related to neural 523 direction encoding as well as to the effects of L-DOPA on these neural signals. We therefore 524 investigated the link between session-specific decoding accuracy and task performance on 525 the last trial, in addition to age group, intervention and session order. Because performance 526 on the last trial was highly confounded with age group (see 2) performance values were 527 demeaned within each age group to investigate effects unrelated to age-specific performance 

In this work we tested the impact of L-DOPA on neural representations of walking direction 554 in younger and older adults, using a double-blind, cross-over intervention design. In addition 555 to a classic decoding approach, we assessed direction specificity of neural signals, a proxy 556 for tuning functions, using the relative structure of classifier probability estimates. Our 557 results revealed that decodability of walking direction signals in the hippocampus and the 558 retrosplenial cortex was enhanced following the administration of L-DOPA. L-DOPA had 559 comparable effects on HC walking direction signals in both age groups, but in the RSC these 560 DA effects were present only in YA. No L-DOPA effects were found in visual cortex (EVC) .

Yet, behavioral investigations showed that in younger adults, EVC direction decoding was 562 related to task performance (spatial distance error), and that L-DOPA related changes in 563 EVC decoding were related to changes in task performance. An investigation of tuning 564 specificity revealed no main effects of L-DOPA or L-DOPA × age group interactions.

Furthermore, decoding across interventions, we found evidence for stable direction sig-566 nals in EVC and RSC, and so some extent also in HPC. Investigating age group differences, 567 we found higher classification accuracy and precision of tuning functions in the EVC of YA 568 compared to OA, a sign of neural dedifferentiation. No age effects on decoding in the HPC 569 or RSC were found. These results confirm our previous finding that neural representations 570 of walking direction can be found in EVC and RSC, and that strong age-related differenti-571 ation is present particularly in EVC (Koch et al., 2020) . We also showed that better EVC 572 classification accuracy was related to better performance on task, suggesting an important 573 functional role of this area in our task. 

. Accordingly, DA's influence on neural gain could lead to a stronger separation between 586 signal and noise, which made different stimuli more specific and easier to distinguish for the 587 classifier. It should be noted, however, that we did not find any direct effects of L-DOPA on neural direction tuning specificity, which measures how similar neural patterns are to similar 589 directions. Given the effects of DA on neural gain, we had hypothesized that this measure 590 could be more sensitive to the effects of our intervention, but this was not the case. One 

D1 but not D5 dopamine receptors are critical for LTP, 782 spatial learning, and LTP-induced arc and zif268 expression in the hippocam-783 pus

Accurate and robust brain image 785 alignment using boundary-based registration

Orienting Movements in the Primary Visual Cortex

Integration of the sensory inputs to place cells: What, where, 791 why, and how? Hippocampus

Improved optimization 793 for the robust and accurate linear registration and motion correction of brain 794 images

Increased attention to spatial context increases both place field sta-797 bility and spatial memory

Mindboggling morphometry of human brains

An improved framework for con-888 found regression and filtering for control of motion artifact in the preprocess-889 ing of resting-state functional connectivity data

Degradation of 892 stimulus selectivity of visual cortical cells in senescent rhesus monkeys

Human aging alters the neural computation and representation of space

Aging and KIBRA/WWC1 genotype affect 899 spatial memory processes in a virtual navigation task

Aging and a genetic KI-903 BRA polymorphism interactively affect feedback-and observation-based 904 probabilistic classification learning

cholamine effects: gain, signal-to-noise ratio, and behavior