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1.  Shining light on motivation, emotion, and memory processes 
PMCID: PMC4299452  PMID: 25653603
emotion; reward; motivation; addiction; habits; obesity; optogenetics
2.  Functional connectivity changes during a working memory task in rat via NMF analysis 
Working memory (WM) is necessary in higher cognition. The brain as a complex network is formed by interconnections among neurons. Connectivity results in neural dynamics to support cognition. The first aim is to investigate connectivity dynamics in medial prefrontal cortex (mPFC) networks during WM. As brain neural activity is sparse, the second aim is to find the intrinsic connectivity property in a feature space. Using multi-channel electrode recording techniques, spikes were simultaneously obtained from mPFC of rats that performed a Y-maze WM task. Continuous time series converted from spikes were embedded in a low-dimensional space by non-negative matrix factorization (NMF). mPFC network in original space was constructed by measuring connections among neurons. And the same network in NMF space was constructed by computing connectivity values between the extracted NMF components. Causal density (Cd) and global efficiency (E) were estimated to present the network property. The results showed that Cd and E significantly peaked in the interval right before the maze choice point in correct trials. However, the increase did not emerge in error trials. Additionally, Cd and E in two spaces displayed similar trends in correct trials. The difference was that the measures in NMF space were significantly greater than those in original space. Our findings indicated that the anticipatory changes in mPFC networks may have an effect on future WM behavioral choices. Moreover, the NMF analysis achieves a better characterization for a brain network.
PMCID: PMC4311635
working memory (WM); spikes; functional connectivity; dimensionality reduction; non-negative matrix factorization (NMF)
3.  FRIEND Engine Framework: a real time neurofeedback client-server system for neuroimaging studies 
In this methods article, we present a new implementation of a recently reported FSL-integrated neurofeedback tool, the standalone version of “Functional Real-time Interactive Endogenous Neuromodulation and Decoding” (FRIEND). We will refer to this new implementation as the FRIEND Engine Framework. The framework comprises a client-server cross-platform solution for real time fMRI and fMRI/EEG neurofeedback studies, enabling flexible customization or integration of graphical interfaces, devices, and data processing. This implementation allows a fast setup of novel plug-ins and frontends, which can be shared with the user community at large. The FRIEND Engine Framework is freely distributed for non-commercial, research purposes.
PMCID: PMC4311636
brain computer interface (BCI); real-time fMRI; FSL; neurofeedback; EEG
4.  Different forms of decision-making involve changes in the synaptic strength of the thalamic, hippocampal, and amygdalar afferents to the medial prefrontal cortex 
Decision-making and other cognitive processes are assumed to take place in the prefrontal cortex. In particular, the medial prefrontal cortex (mPFC) is identified in rodents by its dense connectivity with the mediodorsal (MD) thalamus, and because of its inputs from other sites, such as hippocampus and amygdala (Amyg). The aim of this study was to find a putative relationship between the behavior of mice during the performance of decision-making tasks that involve penalties as a consequence of induced actions, and the strength of field postsynaptic potentials (fPSPs) evoked in the prefrontal cortex from its thalamic, hippocampal, and amygdalar afferents. Mice were chronically implanted with stimulating electrodes in the MD thalamus, the hippocampal CA1 area, or the basolateral amygdala (BLA), and with recording electrodes in the prelimbic/infralimbic area of the prefrontal cortex. Additional stimulating electrodes aimed at evoking negative reinforcements were implanted on the trigeminal nerve. FPSPs evoked at the mPFC from the three selected projecting areas during the food/shock decision-making task decreased in amplitude with shock intensity and animals’ avoidance of the reward. FPSPs collected during the operant task also decreased in amplitude (but that evoked by amygdalar stimulation) when lever presses were associated with a trigeminal shock. Results showed a general decrease in the strength of these potentials when animals inhibited their natural or learned appetitive behaviors, suggesting an inhibition of the prefrontal cortex in these conflicting situations.
PMCID: PMC4311640
decision making; medial prefrontal cortex; hippocampus; basolateral amygdala; mediodorsal thalamus; mice; field postsynaptic potentials; associative learning
5.  Spatially specific vs. unspecific disruption of visual orientation perception using chronometric pre-stimulus TMS 
Transcranial magnetic stimulation (TMS) over occipital cortex can impair visual processing. Such “TMS masking” has repeatedly been shown at several stimulus onset asynchronies (SOAs), with TMS pulses generally applied after the onset of a visual stimulus. Following increased interest in the neuronal state-dependency of visual processing, we recently explored the efficacy of TMS at “negative SOAs”, when no visual processing can yet occur. We could reveal pre-stimulus TMS disruption, with results moreover hinting at two separate mechanisms in occipital cortex biasing subsequent orientation perception. Here we extended this work, including a chronometric design to map the temporal dynamics of spatially specific and unspecific mechanisms of state-dependent visual processing, while moreover controlling for TMS-induced pupil covering. TMS pulses applied 60–40 ms prior to a visual stimulus decreased orientation processing independent of stimulus location, while a local suppressive effect was found for TMS applied 30–10 ms pre-stimulus. These results contribute to our understanding of spatiotemporal mechanisms in occipital cortex underlying the state-dependency of visual processing, providing a basis for future work to link pre-stimulus TMS suppression effects to other known visual biasing mechanisms.
PMCID: PMC4311643
TMS; vision; awareness; orientation processing; masking; suppression; biasing; state-dependent
6.  Chronic shifts in the length and phase of the light cycle increase intermittent alcohol drinking in C57BL/6J mice 
Introduction: Shift workers—e.g., health care professionals, truck drivers, and factory workers—are forced to maintain daily cycles at odds with their natural circadian rhythms and as a consequence need to frequently readjust these cycles. This shift work-induced circadian desynchrony (CD) is associated with increased sleep disorders and with alcohol abuse. Nonetheless, it has proven difficult to model CD-induced changes in alcohol consumption in mouse models, which is an important step toward identifying the mechanisms by which CD increases alcohol intake. This study examined whether frequent changes in the light cycle could increase free access alcohol intake in a mouse line that readily consumes alcohol.
Methods: Free access alcohol intake, water intake, and wheel-running activity patterns of male C57BL/6J mice were measured while the mice were maintained on a normal 12HR photoperiod for baseline data for 2 weeks. The mice were then exposed to an alternating photoperiod of 12 h and 18 h, with light onset advanced 8 h during the 18HR photoperiod. The photoperiods rotated every 3 days, for 21 days total.
Results: The repeated pattern of phase advances and delays, with a concurrent change in the length of the photoperiod, shifted mice to a pattern of intermittent alcohol drinking without altering water intake. Wheel running activity demonstrated that mice were unable to reset their behavioral clocks during CD, showing constant, low-level activity with no peak in activity at the start of the dark phase and greater activity during the morning light phase.
Conclusion: It is possible to model CD effects on alcohol intake in C57BL/6J mice using a pattern of phase shifts and changes in the photoperiod. Using this model, we demonstrate that mice begin intermittent drinking during CD, and this increase in alcohol intake does not correlate with an increase in overall activity or in overall fluid intake.
PMCID: PMC4315044
alcoholism; circadian rhythms; mouse model; addiction; environmental desynchrony
7.  The cortisol response to exercise in young adults 
PMCID: PMC4315045
resistance exercise; cognition; cortisol; hypothalamo-hypophyseal system; young adults
8.  Extending peripersonal space representation without tool-use: evidence from a combined behavioral-computational approach 
Stimuli from different sensory modalities occurring on or close to the body are integrated in a multisensory representation of the space surrounding the body, i.e., peripersonal space (PPS). PPS dynamically modifies depending on experience, e.g., it extends after using a tool to reach far objects. However, the neural mechanism underlying PPS plasticity after tool use is largely unknown. Here we use a combined computational-behavioral approach to propose and test a possible mechanism accounting for PPS extension. We first present a neural network model simulating audio-tactile representation in the PPS around one hand. Simulation experiments showed that our model reproduced the main property of PPS neurons, i.e., selective multisensory response for stimuli occurring close to the hand. We used the neural network model to simulate the effects of a tool-use training. In terms of sensory inputs, tool use was conceptualized as a concurrent tactile stimulation from the hand, due to holding the tool, and an auditory stimulation from the far space, due to tool-mediated action. Results showed that after exposure to those inputs, PPS neurons responded also to multisensory stimuli far from the hand. The model thus suggests that synchronous pairing of tactile hand stimulation and auditory stimulation from the far space is sufficient to extend PPS, such as after tool-use. Such prediction was confirmed by a behavioral experiment, where we used an audio-tactile interaction paradigm to measure the boundaries of PPS representation. We found that PPS extended after synchronous tactile-hand stimulation and auditory-far stimulation in a group of healthy volunteers. Control experiments both in simulation and behavioral settings showed that the same amount of tactile and auditory inputs administered out of synchrony did not change PPS representation. We conclude by proposing a simple, biological-plausible model to explain plasticity in PPS representation after tool-use, which is supported by computational and behavioral data.
PMCID: PMC4313698
peripersonal space; tool-use; neural network model; multisensory processing; plasticity
9.  Dietary intake alters behavioral recovery and gene expression profiles in the brain of juvenile rats that have experienced a concussion 
Concussion and mild traumatic brain injury (mTBI) research has made minimal progress diagnosing who will suffer from lingering symptomology or generating effective treatment strategies. Research demonstrates that dietary intake affects many biological systems including brain and neurological health. This study determined if exposure to a high fat diet (HFD) or caloric restriction (CR) altered post-concussion susceptibility or resiliency using a rodent model of pediatric concussion. Rats were maintained on HFD, CR, or standard diet (STD) throughout life (including the prenatal period and weaning). At postnatal day 30, male and female rats experienced a concussion or a sham injury which was followed by 17 days of testing. Prefrontal cortex and hippocampus tissue was collected for molecular profiling. Gene expression changes in BDNF, CREB, DNMT1, FGF-2, IGF1, LEP, PGC-1α, SIRT1, Tau, and TERT were analyzed with respect to injury and diet. Analysis of telomere length (TL) using peripheral skin cells and brain tissue found that TL in skin significantly correlated with TL in brain tissue and TL was affected by dietary intake and injury status. With respect to mTBI outcomes, diet was correlated with recovery as animals on the HFD often displayed poorer performance than animals on the CR diet. Molecular analysis demonstrated that diet induced epigenetic changes that can be associated with differences in individual predisposition and resiliency to post-concussion syndrome.
PMCID: PMC4318392
caloric restriction; high fat diet; mild traumatic brain injury; qRT-PCR; telomere; sex-differences
10.  Seeking pleasant touch: neural correlates of behavioral preferences for skin stroking 
Affective touch is a dynamic process. In this fMRI study we investigated affective touch by exploring its effects on overt behavior. Arm and palm skin were stroked with a soft brush at five different velocities (0.3, 1, 10, 3, and 30 cm s−1), using a novel feedback-based paradigm. Following stimulation in each trial, participants actively chose whether the caress they would receive in the next trial would be the same speed (“repeat”) or different (“change”). Since preferred stroking speeds should be sought with greater frequency than non-preferred speeds, this paradigm provided a measure of such preferences in the form of active choices. The stimulation velocities were implemented with respect to the differential subjective pleasantness ratings they elicit in healthy subjects, with intermediate velocities (1, 10, and 3 cm s−1) considered more pleasant than very slow or very fast ones. Such pleasantness ratings linearly correlate with changes in mean firing rates of unmyelinated low-threshold C-tactile (CT) afferent nerves in the skin. Here, gentle, dynamic stimulation optimal for activating CT-afferents not only affected behavioral choices, but engaged brain regions involved in reward-related behavior and decision-making. This was the case for both hairy skin of the arm, where CTs are abundant, and glabrous skin of the palm, where CTs are absent. These findings provide insights on central and behavioral mechanisms underlying the perception of affective touch, and indicate that seeking affective touch involves value-based neural processing that is ultimately reflected in behavioral preferences.
PMCID: PMC4318429
fMRI; CT afferents; affective touch; seeking behavior; interoception
11.  High interindividual variability in dose-dependent reduction in speed of movement after exposing C. elegans to shock waves 
In blast-related mild traumatic brain injury (br-mTBI) little is known about the connections between initial trauma and expression of individual clinical symptoms. Partly due to limitations of current in vitro and in vivo models of br-mTBI, reliable prediction of individual short- and long-term symptoms based on known blast input has not yet been possible. Here we demonstrate a dose-dependent effect of shock wave exposure on C. elegans using shock waves that share physical characteristics with those hypothesized to induce br-mTBI in humans. Increased exposure to shock waves resulted in decreased mean speed of movement while increasing the proportion of worms rendered paralyzed. Recovery of these two behavioral symptoms was observed during increasing post-traumatic waiting periods. Although effects were observed on a population-wide basis, large interindividual variability was present between organisms exposed to the same highly controlled conditions. Reduction of cavitation by exposing worms to shock waves in polyvinyl alcohol resulted in reduced effect, implicating primary blast effects as damaging components in shock wave induced trauma. Growing worms on NGM agar plates led to the same general results in initial shock wave effect in a standard medium, namely dose-dependence and high interindividual variability, as raising worms in liquid cultures. Taken together, these data indicate that reliable prediction of individual clinical symptoms based on known blast input as well as drawing conclusions on blast input from individual clinical symptoms is not feasible in br-mTBI.
PMCID: PMC4319468
C. elegans; mild traumatic brain injury; blast trauma; shock wave; locomotion; paralysis; tracking
12.  Greater general startle reflex is associated with greater anxiety levels: a correlational study on 111 young women 
Startle eyeblink reflex is a valid non-invasive tool for studying attention, emotion and psychiatric disorders. In the absence of any experimental manipulation, the general (or baseline) startle reflex shows a high inter-individual variability, which is often considered task-irrelevant and therefore normalized across participants. Unlike the above view, we hypothesized that greater general startle magnitude is related to participants’ higher anxiety level. 111 healthy young women, after completing the State-Trait Anxiety Inventory (STAI), were randomly administered 10 acoustic white noise probes (50 ms, 100 dBA acoustic level) while integrated EMG from left and right orbicularis oculi was recorded. Results showed that participants with greater state anxiety levels exhibited larger startle reflex magnitude from the left eye (r109 = 0.23, p < 0.05). Furthermore, individuals who perceived the acoustic probe as more aversive reported the largest anxiety scores (r109 = 0.28, p < 0.05) and had the largest eyeblinks, especially in the left eye (r109 = 0.34, p < 0.001). Results suggest that general startle may represent a valid tool for studying the neural excitability underlying anxiety and emotional dysfunction in neurological and mental disorders.
PMCID: PMC4319476
anxiety; baseline startle reflex; emotion; EMG; laterality; noise aversiveness
13.  The effect of retrosplenial cortex lesions in rats on incidental and active spatial learning 
The study examined the importance of the retrosplenial cortex for the incidental learning of the spatial arrangement of distinctive features within a scene. In a modified Morris water-maze, rats spontaneously learnt the location of an escape platform prior to swimming to that location. For this, rats were repeatedly placed on a submerged platform in one corner of either a rectangular (Experiment 1) or square (Experiments 2, 3) pool with walls of different appearance. The rats were then released in the center of the pool for their first test trial. In Experiment 1, the correct corner and its diagonally opposite partner (also correct) were specified by the geometric properties of the pool. Rats with retrosplenial lesions took longer to first reach a correct corner, subsequently showing an attenuated preference for the correct corners. A reduced preference for the correct corner was also found in Experiment 2, when platform location was determined by the juxtaposition of highly salient visual cues (black vs. white walls). In Experiment 3, less salient visual cues (striped vs. white walls) led to a robust lesion impairment, as the retrosplenial lesioned rats showed no preference for the correct corner. When subsequently trained actively to swim to the correct corner over successive trials, retrosplenial lesions spared performance on all three discriminations. The findings not only reveal the importance of the retrosplenial cortex for processing various classes of visuospatial information but also highlight a broader role in the incidental learning of the features of a spatial array, consistent with the translation of scene information.
PMCID: PMC4319482
retrosplenial cortex; scene learning; navigation; cingulate cortex; visuospatial memory
14.  Water associated zero maze: a novel rat test for long term traumatic re-experiencing 
Often, freezing and startle behaviors in the context of a previously experienced stress are taken as an indication of post-traumatic stress disorder (PTSD)-like symptoms in rats. However, PTSD is characterized by large individual variations of symptoms. In order to take into consideration the complex and long term distinctive variations in effects of trauma exposure additional behavioral measures are required. The current study used a novel behavioral test, the water associated zero maze (WAZM). This test was planned to enable a formation of an association between the context of the maze and an underwater trauma (UWT) or swim stress in order to examine the impact of exposure to the context which immediately precedes a stressful or a traumatic experience on rat's complex behavior. Rats were exposed to the WAZM and immediately after to an UWT or short swim. One month later rats were re-exposed to the context of the WAZM while their behavior was video recorded. Furthermore, c-Fos expression in the amygdala was measured 90 min after this exposure. The results of the current study indicate that the WAZM can be used to discern behavioral changes measured a long time after the actual traumatic or stressful events. Furthermore, the behavioral changes detected were accompanied by changes of c-Fos expression in the amygdala of exposed rats. We suggest that the WAZM can be used to model traumatic memories re-experiencing in rodent models of human stress-related pathologies such as PTSD.
PMCID: PMC3894455  PMID: 24478648
WAZM; traumatic re-experiencing; amygdala; PTSD; rat model
15.  Neurosonological Examination: A Non-Invasive Approach for the Detection of Cerebrovascular Impairment in AD 
There has been a growing interest in vascular impairment associated with Alzheimer’s disease (AD). This interest was stimulated by the findings of higher incidence of vascular risk factors in AD. Signs of vascular impairment were investigated notably in the field of imaging methods. Our aim was to explore ultrasonographic studies of extra- and intracranial vessels in patients with AD and mild cognitive impairment (MCI) and define implications for diagnosis, treatment, and prevention of the disease. The most frequently studied parameters with extracranial ultrasound are intima-media thickness in common carotid artery, carotid atherosclerosis, and total cerebral blood flow. The transcranial ultrasound concentrates mostly on flow velocities, pulsatility indices, cerebrovascular reserve capacity, and cerebral microembolization. Studies suggest that there is morphological and functional impairment of cerebral circulation in AD compared to healthy subjects. Ultrasound as a non-invasive method could be potentially useful in identifying individuals in a higher risk of progression of cognitive decline.
PMCID: PMC3896883  PMID: 24478651
Alzheimer’s disease; carotid ultrasound; cerebrovascular reserve capacity; neurosonology; transcranial ultrasound
16.  Amygdala activation and GABAergic gene expression in hippocampal sub-regions at the interplay of stress and spatial learning 
Molecular processes in GABAergic local circuit neurons critically contribute to information processing in the hippocampus and to stress-induced activation of the amygdala. In the current study, we determined expression changes in GABA-related factors induced in subregions of the dorsal hippocampus as well as in the BLA of rats 5 h after spatial learning in a Morris water maze (MWM), using laser microdissection and quantitative real-time PCR. Spatial learning resulted in highly selective pattern of changes in hippocampal subregions: gene expression levels of neuropeptide Y (NPY) were reduced in the hilus of the dentate gyrus (DG), whereas somatostatin (SST) was increased in the stratum oriens (SO) of CA3. The GABA-synthesizing enzymes GAD65 and GAD67 as well as the neuropeptide cholecystokinin (CCK) were reduced in SO of CA1. In the BLA, expression of GAD65 and GAD67 were reduced compared to a handled Control group. These expression patterns were further compared to alterations in a group of rats that have been exposed to the water maze but were not provided with an invisible escape platform. In this Water Exposure group, no expression changes were observed in any of the hippocampal subregions, but a differential regulation of all selected target genes was evident in the BLA. These findings suggest that expression changes of GABAergic factors in the hippocampus are associated with spatial learning, while additional stress effects modulate expression alterations in the BLA. Indeed, while in both experimental groups plasma corticosterone (CORT) levels were enhanced, only Water Exposure stress activated the basolateral amygdala (BLA), as indicated by increased levels of phosphorylated ERK 1/2. Altered GABAergic function in the BLA may thus contribute to memory consolidation in the hippocampus, in relation to levels of stress and emotionality associated with the experience.
PMCID: PMC3896990  PMID: 24478650
basolateral amygdala; hippocampus; Morris water maze (MWM); stress; interneuron; gene expression; rat
17.  VTA GABA neurons modulate specific learning behaviors through the control of dopamine and cholinergic systems 
The mesolimbic reward system is primarily comprised of the ventral tegmental area (VTA) and the nucleus accumbens (NAc) as well as their afferent and efferent connections. This circuitry is essential for learning about stimuli associated with motivationally-relevant outcomes. Moreover, addictive drugs affect and remodel this system, which may underlie their addictive properties. In addition to dopamine (DA) neurons, the VTA also contains approximately 30% γ-aminobutyric acid (GABA) neurons. The task of signaling both rewarding and aversive events from the VTA to the NAc has mostly been ascribed to DA neurons and the role of GABA neurons has been largely neglected until recently. GABA neurons provide local inhibition of DA neurons and also long-range inhibition of projection regions, including the NAc. Here we review studies using a combination of in vivo and ex vivo electrophysiology, pharmacogenetic and optogenetic manipulations that have characterized the functional neuroanatomy of inhibitory circuits in the mesolimbic system, and describe how GABA neurons of the VTA regulate reward and aversion-related learning. We also discuss pharmacogenetic manipulation of this system with benzodiazepines (BDZs), a class of addictive drugs, which act directly on GABAA receptors located on GABA neurons of the VTA. The results gathered with each of these approaches suggest that VTA GABA neurons bi-directionally modulate activity of local DA neurons, underlying reward or aversion at the behavioral level. Conversely, long-range GABA projections from the VTA to the NAc selectively target cholinergic interneurons (CINs) to pause their firing and temporarily reduce cholinergic tone in the NAc, which modulates associative learning. Further characterization of inhibitory circuit function within and beyond the VTA is needed in order to fully understand the function of the mesolimbic system under normal and pathological conditions.
PMCID: PMC3897868  PMID: 24478655
benzodiazepine; dopamine; acetylcholine; NAc; VTA; interneuron; pharmacogenetics; optogenetics
18.  Stress leads to prosocial action in immediate need situations 
Stress clearly influences decision making, but the effects are complex. This review focuses on the potential for stress to promote prosocial decisions, serving others at a temporary cost to the self. Recent work has shown altruistic responses under stress, particularly when the target’s need is salient. We discuss potential mechanisms for these effects, including emotional contagion and offspring care mechanisms. These neurobiological mechanisms may promote prosocial—even heroic—action, particularly when an observer knows the appropriate response and can respond to a target in need. The effects of stress on behavior are not only negative, they can be adaptive and altruistic under conditions that promote survival and well-being at the individual and group level.
PMCID: PMC3897879  PMID: 24478652
stress; decision making; altruism; empathy; TSST; perception-action
19.  Reduced Expression of Nogo-A Leads to Motivational Deficits in Rats 
Nogo-A is an important neurite growth-regulatory protein in the adult and developing nervous system. Mice lacking Nogo-A, or rats with neuronal Nogo-A deficiency, exhibit behavioral abnormalities such as impaired short-term memory, decreased pre-pulse inhibition, and behavioral inflexibility. In the current study, we extended the behavioral profile of the Nogo-A deficient rat line with respect to reward sensitivity and motivation, and determined the concentrations of the monoamines dopamine and serotonin in the prefrontal cortex (PFC), dorsal striatum (dSTR), and nucleus accumbens (NAcc). Using a limited access consumption task, we found similar intake of a sweet condensed milk solution following ad libitum or restricted feeding in wild-type and Nogo-A deficient rats, indicating normal reward sensitivity and translation of hunger into feeding behavior. When tested for motivation in a spontaneous progressive ratio task, Nogo-A deficient rats exhibited lower break points and tended to have lower “highest completed ratios.” Further, under extinction conditions responding ceased substantially earlier in these rats. Finally, in the PFC we found increased tissue levels of serotonin, while dopamine was unaltered. Dopamine and serotonin levels were also unaltered in the dSTR and the NAcc. In summary, these results suggest a role for Nogo-A regulated processes in motivated behavior and related neurochemistry. The behavioral pattern observed resembles aspects of the negative symptomatology of schizophrenia.
PMCID: PMC3898325  PMID: 24478657
Nogo-A; reward sensitivity; anhedonia; motivation; avolition; schizophrenia; dopamine; serotonin
20.  Detecting Analogies Unconsciously 
Analogies may arise from the conscious detection of similarities between a present and a past situation. In this functional magnetic resonance imaging study, we tested whether young volunteers would detect analogies unconsciously between a current supraliminal (visible) and a past subliminal (invisible) situation. The subliminal encoding of the past situation precludes awareness of analogy detection in the current situation. First, participants encoded subliminal pairs of unrelated words in either one or nine encoding trials. Later, they judged the semantic fit of supraliminally presented new words that either retained a previously encoded semantic relation (“analog”) or not (“broken analog”). Words in analogs versus broken analogs were judged closer semantically, which indicates unconscious analogy detection. Hippocampal activity associated with subliminal encoding correlated with the behavioral measure of unconscious analogy detection. Analogs versus broken analogs were processed with reduced prefrontal but enhanced medial temporal activity. We conclude that analogous episodes can be detected even unconsciously drawing on the episodic memory network.
PMCID: PMC3898596  PMID: 24478656
episodic memory; subliminal; analogical mapping; consciousness; flexibility; hippocampus; medial temporal lobe
21.  In your eyes only: deficits in executive functioning after frontal TMS reflect in eye movements 
This study investigated the roles of the right and left dorsolateral prefrontal (rDLPFC, lDLPFC) and the medial frontal cortex (MFC) in executive functioning using a theta burst transcranial magnetic stimulation (TMS) approach. Healthy subjects solved two visual search tasks: a number search task with low cognitive demands, and a number and letter search task with high cognitive demands. To observe how subjects solved the tasks, we assessed their behavior with and without TMS using eye movements when subjects were confronted with specific executive demands. To observe executive functions, we were particularly interested in TMS-induced changes in visual exploration strategies found to be associated with good or bad performance in a control condition without TMS stimulation. TMS left processing time unchanged in both tasks. Inhibition of the rDLPFC resulted in a decrease in anticipatory fixations in the number search task, i.e., a decrease in a good strategy in this low demand task. This was paired with a decrease in stimulus fixations. Together, these results point to a role of the rDLPFC in planning and response selection. Inhibition of the lDLPFC and the MFC resulted in an increase in anticipatory fixations in the number and letter search task, i.e., an increase in the application of a good strategy in this task. We interpret these results as a compensatory strategy to account for TMS-induced deficits in attentional switching when faced with high switching demands. After inhibition of the lDLPFC, an increase in regressive fixations was found in the number and letter search task. In the context of high working memory demands, this strategy appears to support TMS-induced working memory deficits. Combining an experimental TMS approach with the recording of eye movements proved sensitive to discrete decrements of executive functions and allows pinpointing the functional organization of the frontal lobes.
PMCID: PMC3902210  PMID: 24478654
eye movements; executive functions; theta burst TMS; dorsolateral prefrontal cortex; medial frontal cortex
22.  The neuronal and molecular basis of quinine-dependent bitter taste signaling in Drosophila larvae 
The sensation of bitter substances can alert an animal that a specific type of food is harmful and should not be consumed. However, not all bitter compounds are equally toxic and some may even be beneficial in certain contexts. Thus, taste systems in general may have a broader range of functions than just in alerting the animal. In this study we investigate bitter sensing and processing in Drosophila larvae using quinine, a substance perceived by humans as bitter. We show that behavioral choice, feeding, survival, and associative olfactory learning are all directly affected by quinine. On the cellular level, we show that 12 gustatory sensory receptor neurons that express both GR66a and GR33a are required for quinine-dependent choice and feeding behavior. Interestingly, these neurons are not necessary for quinine-dependent survival or associative learning. On the molecular receptor gene level, the GR33a receptor, but not GR66a, is required for quinine-dependent choice behavior. A screen for gustatory sensory receptor neurons that trigger quinine-dependent choice behavior revealed that a single GR97a receptor gene expressing neuron located in the peripheral terminal sense organ is partially necessary and sufficient. For the first time, we show that the elementary chemosensory system of the Drosophila larva can serve as a simple model to understand the neuronal basis of taste information processing on the single cell level with respect to different behavioral outputs.
PMCID: PMC3902218  PMID: 24478653
Drosophila larvae; gustation; bitter; single cell; gustatory receptors; feeding; learning and memory
23.  Effect of Meditation on Cognitive Functions in Context of Aging and Neurodegenerative Diseases 
Effect of different meditation practices on various aspects of mental and physical health is receiving growing attention. The present paper reviews evidence on the effects of several mediation practices on cognitive functions in the context of aging and neurodegenerative diseases. The effect of meditation in this area is still poorly explored. Seven studies were detected through the databases search, which explores the effect of meditation on attention, memory, executive functions, and other miscellaneous measures of cognition in a sample of older people and people suffering from neurodegenerative diseases. Overall, reviewed studies suggested a positive effect of meditation techniques, particularly in the area of attention, as well as memory, verbal fluency, and cognitive flexibility. These findings are discussed in the context of MRI studies suggesting structural correlates of the effects. Meditation can be a potentially suitable non-pharmacological intervention aimed at the prevention of cognitive decline in the elderly. However, the conclusions of these studies are limited by their methodological flaws and differences of various types of meditation techniques. Further research in this direction could help to verify the validity of the findings and clarify the problematic aspects.
PMCID: PMC3903052  PMID: 24478663
meditation; cognition; dementia; aging; neurodegenerative diseases; Alzheimer’s disease; mild cognitive impairment; elderly
24.  Effects of caffeine or RX821002 in rats with a neonatal ventral hippocampal lesion 
Rats with a neonatal ventral hippocampal lesion (NVHL) are used to model schizophrenia. They show enhanced locomotion and difficulties in learning after puberty. Such behavioral modifications are strengthened by dopaminergic psychostimulant drugs, which is also relevant for schizophrenia because illustrating its dopaminergic facet. But it remains questionable that only dopaminergic drugs elicit such effects. The behavioral effects could simply represent a non specific arousal, in which case NVHL rats should also be hyper-responsive to other vigilance enhancing drugs. We administered an adenosine (caffeine) or an adrenaline receptor antagonist, (RX821002) at doses documented to modify alertness of rats, respectively 5 mg/kg and 1 mg/kg. Rats were selected prior to the experiments using magnetic resonance imaging (MRI). Each group contained typical and similar NVHL lesions. They were compared to sham lesioned rats. We evaluated locomotion in a new environment and the capacity to remember a visual or acoustic cue that announced the occurrence of food. Both caffeine and RX82100 enhanced locomotion in the novel environment, particularly in NVHL rats. But, RX82100 had a biphasic effect on locomotion, consisting of an initial reduction preceding the enhancement. It was independent of the lesion. Caffeine did not modify the learning performance of NVHL rats. But, RX821002 was found to facilitate learning. Patients tend to intake much more caffeine than healthy people, which has been interpreted as a means to counter some cognitive deficits. This idea was not validated with the present results. But adrenergic drugs could be helpful for attenuating some of their cognitive deficits.
PMCID: PMC3904090  PMID: 24478661
animal model of schizophrenia; ventral hippocampal lesion; xanthine; noradrenaline; dopamine; therapy
25.  Not all effort is equal: the role of the anterior cingulate cortex in different forms of effort-reward decisions 
The rat anterior cingulate cortex (ACC) mediates effort-based decision making when the task requires the physical effort of climbing a ramp. Normal rats will readily climb a barrier leading to high reward whereas rats with ACC lesions will opt instead for an easily obtained small reward. The present study explored whether the role of ACC in cost-benefit decisions extends beyond climbing by testing its role in ramp climbing as well as two novel cost-benefit decision tasks, one involving the physical effort of lifting weights and the other the emotional cost of overcoming fear (i.e., “courage”). As expected, rats with extensive ACC lesions tested on a ramp-climbing task were less likely to choose a high-reward/high-effort arm than sham controls. However, during the first few trials, lesioned rats were as likely as controls to initially turn into the high-reward arm (HRA) but far less likely to actually climb the barrier, suggesting that the role of the ACC is not in deciding which course of action to pursue, but rather in maintaining a course of action in the face of countervailing forces. In the effort-reward decision task involving weight lifting, some lesion animals behaved like controls while others avoided the HRA. However, the results were not statistically significant and a follow-up study using incremental increasing effort failed to show any difference between lesion and control groups. The results suggest that the ACC is not needed for effort-reward decisions involving weight lifting but may affect motor abilities. Finally, a courage task explored the willingness of rats to overcome the fear of crossing an open, exposed arm to obtain a high reward. Both sham and ACC-lesioned animals exhibited equal tendencies to enter the open arm. However, whereas sham animals gradually improved on the task, ACC-lesioned rats did not. Taken together, the results suggest that the role of the ACC in effort-reward decisions may be limited to certain tasks.
PMCID: PMC3904092  PMID: 24478659
anterior cingulate; effort; decision making; courage

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