Selective Disruption of Perineuronal Nets in Mice Lacking Crtl1 is Sufficient to Make Fear Memories Susceptible to Erasure

The ability to store, retrieve, and extinguish memories of adverse experiences is an essential skill for animals' survival. The cellular and molecular factors that underlie such processes are only partially known. Using chondroitinase ABC treatment targeting chondroitin sulfate proteoglycans (CSPGs), previous studies showed that the maturation of the extracellular matrix makes fear memory resistant to deletion. Mice lacking the cartilage link protein Crtl1 (Crtl1-KO mice) display normal CSPG levels but impaired CSPG condensation in perineuronal nets (PNNs). Thus, we asked whether the presence of PNNs in the adult brain is responsible for the appearance of persistent fear memories by investigating fear extinction in Crtl1-KO mice. We found that mutant mice displayed fear memory erasure after an extinction protocol as revealed by analysis of freezing and pupil dynamics. Fear memory erasure did not depend on passive loss of retention; moreover, we demonstrated that, after extinction training, conditioned Crtl1-KO mice display no neural activation in the amygdala (Zif268 staining) in comparison to control animals. Taken together, our findings suggest that the aggregation of CSPGs into PNNs regulates the boundaries of the critical period for fear extinction

It's the intention that matters : neural representations of learning from intentional harm in social interactions

As a social species, humans are not only driven by the pursuit of necessities such as food and shelter, but also complex processes such as social interactions. To navigate our everyday life, we use information gathered throughout a lifetime of social interactions in which we learn from others and their actions but also, and not less importantly, about others. To create a complete picture of a social interaction, we assess the individual we interact with, make judgements about them and their actions, and integrate what we know with the consequences of their actions. This way, we learn the relationship between events (e.g. others’ actions) and environmental stimuli, such as other individuals that predict the actions. As we encounter more people and go through more interactions, we continuously update information stored in memory from previous experiences. A common task, for example, going through the busy corridor in our workplace in a hurry does not only include avoiding physical harm caused by bumping into the coffee machine with a sharp corner, but also avoiding a co-worker we are in a feud with, and whom we believed knowingly spilled hot coffee on another co-worker the week before. How social information is processed is key in understanding rarer but more impactful events that can have lifelong impact on an individual’s life. Interpersonal trauma, a type of trauma that is acquired from harm received from another individual, leads more often to post-traumatic stress disorder (PTSD) than non-socially related trauma, for example, a car crash (Kleim, Ehlers, & Glucksman, 2007). To understand why a specific social harm affect us negatively, it is crucial to study how the brain integrates social, as well as nonsocial (physical) information during the harmful event. In Study I, II, and III we investigated how different streams of information (social and physical) are integrated during a social interaction. We were interested in how intentionality of an action that has direct aversive consequences on an individual can change the individuals’ judgements of the action and the person performing it. Using a time-based neuroimaging approach, we investigated how the value of an action is integrated with that of the intention behind it. Study I revealed evidence that suggests that intentionality of a directly experienced aversive action is represented throughout the cortex in neural activity patterns that form over time. Study II highlighted the importance of timing and sample size in similar paradigms, and that neural pattern formation in response to aversive actions regardless of the intentions behind them are robustly replicated. In Study III we asked questions about how these learned action outcomes and knowledge about the people performing the harmful action change neural connectivity, and how this translates into changes in perception and memory 24-hours later. We found an increased connectivity between the hippocampus and the amygdala, which correlated with generalized memory responses to images associated with shocks from an intentional harm do-er, and increased connectivity between the FFA and the insula, as well as the FFA and the dorsomedial prefrontal cortex (dmPFC) correlated with facilitated recognition of the intentional harm do-er’s face

Chronic noise stress affects neocortical and hippocampal-amygdala functional connectivity in mice

This thesis examines the effects of chronic noise stress on neocortical and hippocampal-amygdala networks and their behavioural correlates. Psychological symptoms of stress, including anxiety and depression, are thought to be caused by alterations in functional connectivity within the brain. A functional pathway has been established between the basolateral amygdala, which mediates emotional responses to stressors, the ventral hippocampus which provides context to emotional memories and experiences, and medial prefrontal cortex, which alters attention and perception of stressors. This network is adaptive in the presence of an acute stressor, allowing an organism to optimally prepare and deal with the source of stress, but may become dysfunctional when exposed to chronic stress. The hypotheses that chronic noise stress correlates to neocortical hyperconnectivity and decreased synchrony between the amygdala and hippocampus, correlates to altered behaviour, and correlates to altered brain morphology were tested in head-fixed mice using optical imaging and behavioural recordings

Simultaneous pupillometry and functional Magnetic Resonance Imaging (fMRI) for the detection of stress-related endophenotypes

Mental diseases constitute a core health challenge of the 21st century. To date, diagnostics in psychiatry have been primarily based on subjective self-reports, largely bypassing the biological underpinnings and phenotypic heterogeneity of psychiatric disorders. As an effort to implement a more biologically valid classification of mental disorders, recent initiatives like the Research Domain Criteria (RDoC) project aim to identify endophenotypes that reflect transdiagnostic core mechanisms of psychiatric disorders. Stress is known to play a fundamental role in the development of mood and anxiety disorders. One key system involved in the physiological response to stress is the brainstem?s noradrenergic (NA) arousal center located in the locus coeruleus (LC), and previous studies indicate that pupil size provides an indirect index for activity of the LC-NA system. In order to investigate the relationship between spontaneous drifts in autonomic arousal and global brain activity in healthy human subjects, we first determined the fMRI correlates of spontaneous pupil fluctuations during the resting state. We found that pupil dilations are strongly coupled to activation of the dorsal anterior cingulate cortex (dACC) and bilateral insula (salience network [SN]). To assess whether this link between the pupil and the SN would also extend to emotional arousal, we next investigated the neural correlates of reward anticipation-induced pupil dilations in healthy subjects. Here, we could show that a cue signaling the possibility to receive a monetary reward evoked strong pupil dilations, the magnitude of which predicted response time to a target cue. Again, pupil dilations were strongly linked to SN activation. Furthermore, our results suggest that pupillometry is helpful to dissect different phases of reward anticipation and associated brain activity, disentangling reward prediction, arousal modulation and attentionrelated processes. These observations led us to the conclusion that the SN modulates arousal levels to optimize task performance, that is, to counteract drowsiness/ transitions to sleep during the resting state and to facilitate reward-directed behaviors in the reward anticipation task. Taken together, pupillometry appears to provide a reliable index for activity of the SN, a core network related to psychiatric disorders, making it a promising tool for the detection of stress-related endophenotypes

Neural correlates of pupil dilation during human fear learning

Background: Fear conditioning and extinction are prevailing experimental and etiological models for normal and pathological anxiety. Pupil dilations in response to conditioned stimuli are increasingly used as a robust psychophysiological readout of fear learning, but their neural correlates remain unknown. We aimed at identifying the neural correlates of pupil responses to threat and safety cues during a fear learning task. Methods: Thirty-four healthy subjects underwent a fear conditioning and extinction paradigm with simultaneous functional magnetic resonance imaging (fMRI) and pupillometry. After a stringent preprocessing and artifact rejection procedure, trial-wise pupil responses to threat and safety cues were entered as parametric modulations to the fMRI general linear models. Results: Trial-wise magnitude of pupil responses to both conditioned and safety stimuli correlated positively with activity in dorsal anterior cingulate cortex (dACC), thalamus, supramarginal gyrus and insula for the entire fear learning task, and with activity in the dACC during the fear conditioning phase in particular. Phasic pupil responses did not show habituation, but were negatively correlated with tonic baseline pupil diameter, which decreased during the task. Correcting phasic pupil responses for the tonic baseline pupil diameter revealed thalamic activity, which was also observed in an analysis employing a linear (declining) time modulation. Conclusion: Pupil dilations during fear conditioning and extinction provide useful readouts to track fear learning on a trial-by-trial level, particularly with simultaneous fMRI. Whereas phasic pupil responses reflect activity in brain regions involved in fear learning and threat appraisal, most prominently in dACC, tonic changes in pupil diameter may reflect changes in general arousal

Predictive cognition in dementia: the case of music

The clinical complexity and pathological diversity of neurodegenerative diseases impose immense challenges for diagnosis and the design of rational interventions. To address these challenges, there is a need to identify new paradigms and biomarkers that capture shared pathophysiological processes and can be applied across a range of diseases. One core paradigm of brain function is predictive coding: the processes by which the brain establishes predictions and uses them to minimise prediction errors represented as the difference between predictions and actual sensory inputs. The processes involved in processing unexpected events and responding appropriately are vulnerable in common dementias but difficult to characterise. In my PhD work, I have exploited key properties of music – its universality, ecological relevance and structural regularity – to model and assess predictive cognition in patients representing major syndromes of frontotemporal dementia – non-fluent variant PPA (nfvPPA), semantic-variant PPA (svPPA) and behavioural-variant FTD (bvFTD) - and Alzheimer’s disease relative to healthy older individuals. In my first experiment, I presented patients with well-known melodies containing no deviants or one of three types of deviant - acoustic (white-noise burst), syntactic (key-violating pitch change) or semantic (key-preserving pitch change). I assessed accuracy detecting melodic deviants and simultaneously-recorded pupillary responses to these deviants. I used voxel-based morphometry to define neuroanatomical substrates for the behavioural and autonomic processing of these different types of deviants, and identified a posterior temporo-parietal network for detection of basic acoustic deviants and a more anterior fronto-temporo-striatal network for detection of syntactic pitch deviants. In my second chapter, I investigated the ability of patients to track the statistical structure of the same musical stimuli, using a computational model of the information dynamics of music to calculate the information-content of deviants (unexpectedness) and entropy of melodies (uncertainty). I related these information-theoretic metrics to performance for detection of deviants and to ‘evoked’ and ‘integrative’ pupil reactivity to deviants and melodies respectively and found neuroanatomical correlates in bilateral dorsal and ventral striatum, hippocampus, superior temporal gyri, right temporal pole and left inferior frontal gyrus. Together, chapters 3 and 4 revealed new hypotheses about the way FTD and AD pathologies disrupt the integration of predictive errors with predictions: a retained ability of AD patients to detect deviants at all levels of the hierarchy with a preserved autonomic sensitivity to information-theoretic properties of musical stimuli; a generalized impairment of surprise detection and statistical tracking of musical information at both a cognitive and autonomic levels for svPPA patients underlying a diminished precision of predictions; the exact mirror profile of svPPA patients in nfvPPA patients with an abnormally high rate of false-alarms with up-regulated pupillary reactivity to deviants, interpreted as over-precise or inflexible predictions accompanied with normal cognitive and autonomic probabilistic tracking of information; an impaired behavioural and autonomic reactivity to unexpected events with a retained reactivity to environmental uncertainty in bvFTD patients. Chapters 5 and 6 assessed the status of reward prediction error processing and updating via actions in bvFTD. I created pleasant and aversive musical stimuli by manipulating chord progressions and used a classic reinforcement-learning paradigm which asked participants to choose the visual cue with the highest probability of obtaining a musical ‘reward’. bvFTD patients showed reduced sensitivity to the consequence of an action and lower learning rate in response to aversive stimuli compared to reward. These results correlated with neuroanatomical substrates in ventral and dorsal attention networks, dorsal striatum, parahippocampal gyrus and temporo-parietal junction. Deficits were governed by the level of environmental uncertainty with normal learning dynamics in a structured and binarized environment but exacerbated deficits in noisier environments. Impaired choice accuracy in noisy environments correlated with measures of ritualistic and compulsive behavioural changes and abnormally reduced learning dynamics correlated with behavioural changes related to empathy and theory-of-mind. Together, these experiments represent the most comprehensive attempt to date to define the way neurodegenerative pathologies disrupts the perceptual, behavioural and physiological encoding of unexpected events in predictive coding terms