Freie Universität Berlin

Yet another fascinating Nature article from the research group around Gilles Laurent. This article is built around the mechanisms underlying associative learning and plasticity in the mushroom bodies in insects. The area is known to be crucial for associative learning of odors and contains up to hundreds of thousands of neurons called Kenyon cells.
Here the authors focus on synapses between Kenyon cells and beta lobe neurons in the MBs of locusts that are modifiable by a Hebbian spike-timing-dependent plasticity (STDP) rule. Firing of pre- and postsynaptic neuron within a few tens of milliseconds can result in synaptic change (plasticity). The authors argue that “responses to odours recorded in Kenyon cells during behavioural learning generally occur and end well before reward delivery, indicating that STDP alone cannot support associative conditioning”. Cassenaer and Laurent demonstrate that the local delivery of a reinforcement-mediating neuromodulator, in this case octopamine, following the pre–post pairing causing STDP can specify the synapses that will undergo an associative change. Due to the neuromodulator, at these synapses the STDP rule itself is transformed. Octopamine is a biogenic amine involved in insect learning and memory here applied as an injection one second after spike pairing. Kenyon cells were stimulated in vivo using either electrical impulses or odour delivery, with the same outcome.
This research article is commented by Timothy E. Holy in the same Journal.

Cassenaer, S., & Laurent, G. (2012). Conditional modulation of spike-timing-dependent plasticity for olfactory learning Nature, 482 (7383), 47-52 DOI: 10.1038/nature10776

Holy TE (2012). Neuroscience: Reward alters specific connections. Nature, 482 (7383), 39-41 PMID: 22297965

Posted on behalf of Neloy Kumar Chakroborty

Summary: Prefrontal cortex (PFC) is known to be an important area regulating the extinction of fear. Psychostimulants that can increase the extracellular levels of dopamine (DA) in the PFC were reported to be involved in the fear extinction, although the reports were dilemmatic. Methylphenidate hydrochloride (MPH) or Ritalin (trade name) was known to increase the extracellular levels of the DA and norepinephrine (NA) in the PFC and has been approved for the therapy of attention deficit hyperactivity disorder (ADHD). The authors in this article were trying to investigate the effect of the systemic injection of Ritalin both during the pre and post-session of the contextual fear extinction to the development and consolidation of the extinction memory in the mouse model. They found that pre-session injection of MPH had promoted the extinction learning during the training and test trials after 1 day, although the drug had an immediate effect of increasing the overall locomotor activity of animals. Administration of MPH immediately after the extinction session had enhanced the extinction effect over a period of 3 days of retention tests. However, this effect was most obvious with the dosage of 20 mg/kg, although the other doses (both higher and lower) had revealed the enhancement of the fear extinction. The enhancement of fear extinction was neither observer while the drug was applied 4 hours later than the extinction session nor while the time session of the extinction learning trial was shortened which was followed by the MPH injection. The authors had concluded that MPH can enhance the extinction of fear and that this effect was found to be sensitive to dose, time of injection, and duration of the extinction session. Because MPH is widely used in clinical treatments, these experiments had suggested that potential use of the drug in combination with the behavioral therapies for patients with fear disorders.

Reference:
Abraham AD, Cunningham CL, & Lattal KM (2012). Methylphenidate enhances extinction of contextual fear. Learning & memory (Cold Spring Harbor, N.Y.), 19 (2), 67-72 PMID: 22251891

Perceptual decision making is formalized as the accumulation of (noisy) sensory evidence until a decision threshold is crossed. Much understanding has been gained from studies of monkey neurophysiology and human neuroimaging as well as by computational modeling but there are still fascinating open questions about mechanisms of perceptual decision making. Perceptual decisions can be made within a fraction of a second (~ several hundred milliseconds, measured as reaction time (RT) which is usually defined as the time from the onset of the stimulus till the response). However, what part of the highly variable RT is dedicated to the processing of the percept itself, leaving motor preparation, motor execution and sensory latency aside? This is the central problem that Shankar et al.(2011) and Stanford et al.(2010) investigated. In order to isolate this processing step, they developed a new task design, the compelled response paradigm. In this task a participant (here a monkey) is asked to saccade from a fixation point (located in the middle of the presentation screen) to one of two targets. A ‚Go’ signal informs the participant that a saccade has to be initiated (when the fixation point disappears). Importantly, the true color of the targets (which indicates the correct target location) is revealed only after a random delay after the Go signal occurred. The delay is under the control of the experimenter, thus one can now calculate raw and effective processing time, i.e. by subtracting the delay from RT to get the former, and thereby come up with metrics that represent available time for sensory processing. The authors combine behavioral analysis with single neuron recordings and computational modeling to dissociate perceptual evaluation from motor execution.

In summary, the authors establish an original method for estimating pure evidence integration. Furthermore, by using different variations of this task, they show motor and perceptual contributions to decision making.

Stanford, T., Shankar, S., Massoglia, D., Costello, M., & Salinas, E. (2010). Perceptual decision making in less than 30 milliseconds Nature Neuroscience, 13 (3), 379-385 DOI: 10.1038/nn.2485

Shankar, S., Massoglia, D., Zhu, D., Costello, M., Stanford, T., & Salinas, E. (2011). Tracking the Temporal Evolution of a Perceptual Judgment Using a Compelled-Response Task Journal of Neuroscience, 31 (23), 8406-8421 DOI: 10.1523/JNEUROSCI.1419-11.2011

Merel Kindt and her team demonstrated that fear memory can be deleted in humans (Kindt et al. 2009). This was achieved by the oral administration of β-adrenergic receptor antagonist propranolol before the reactivation of memory. They propose that their strategy of disrupting the (re-) stabilization of a memory after retrieval (reconsolidation) could pave the way for a long term cure for patients with emotional disorders. In such a treatment it would be important to have content limited memory deletion. Therefore it is straight forward that Marieke Soeter and Merel Kindt here investigate how aspects of fear generalization are affected by their pharmacological approach of memory erasure. They show that the fear potentiated startle response to the trained and reactivated stimulus is deleted by the administration of propranolol before the reactivation.  In contrast the response to a parallel trained but not reactivated stimulus is not affected.  Further they demonstrate that category related generalization normally occurs. Nevertheless they show that the disruption of reconsolidation changes “the core memory trace” in that way that there is no generalization produced after successful reacquisition. Meaning that the disruption of reconsolidation changes the way stimuli are (re)learned in a successive acquisition.

Additionally the authors challenge the universality of the finding of Schiller and colleagues (D Schiller et al. 2010). Schiller et al provided evidence that fear memories can be deleted by behavioral manipulations in humans. Nevertheless Soeter and Kindt, here using a stronger conditioning protocol (80% vs. 30% reinforcement, fear relevant objects vs. geometric figures), demonstrate that for their paradigm this behavioral manipulation does not erase the memory.

In sum the study suggests that behavioral manipulation does not prevent stronger fear memory from return. However the study shows that the pharmacological disruption of reconsolidation specifically deletes fear memory and its category related aspects.

Soeter, M., & Kindt, M. (2011). Disrupting reconsolidation: Pharmacological and behavioral manipulations Learning & Memory, 18 (6), 357-366 DOI: 10.1101/lm.2148511

This study illustrates the requirement of training and exercise in executing successful fine motor skills in the invertebrates.Fruit fly Drosophila groups reared and grown in two different fly chambers ,one allows free flight movement and other restricted flight movement were tested for various flight kinematics in free flight arena and tethered flight simulator.Overall performance of the experienced flight animals and naive previously unexperienced flight animal seems to be genetically pre-determined except the naive flies showed inefficient fine object tracking and optomotor skills.
The authors proposed two hypothesis based on their findings that support the role of experience in flight namely Neuronal and muscular exercise hypothesis.This study suggests that insects are not just pre determined flight machineries and plasticity shapes the fine motor control.Therefore the plasticity in motor skills should also be of interest for building any biologically inspired devices .

Reference:

Hesselberg, T., & Lehmann, F. (2009). The role of experience in flight behaviour of Drosophila Journal of Experimental Biology, 212 (20), 3377-3386 DOI: 10.1242/jeb.025221

Posted on behalf of Hans-Joachim Pflüger:

In the article by Ott et al. the role of two protein kinases (PK) in the population density dependent transition from solitarious to gregarious animals is investigated. Only gregarious locusts form large swarms that are harmful for agriculture. The foraging gene product, a cGMP-dependent PK (PKG), implicated in foraging, and a cAMP-dependent PK (PKA), for example involved in processes of learning, were examined. The main result is that PKA but not PKG is involved in this phase transition between solitarious and gregarious animals.

Ott, S., Verlinden, H., Rogers, S., Brighton, C., Quah, P., Vleugels, R., Verdonck, R., & Vanden Broeck, J. (2011). Critical role for protein kinase A in the acquisition of gregarious behavior in the desert locust Proceedings of the National Academy of Sciences DOI: 10.1073/pnas.1114990109

Posted on behalf of Jaime Martinez:

The authors of the present work studied the extent to which visual brain regions participate in non-sensory cognitive processes of visual representation. To this end, they evaluated the role of ventral visual pathway areas in visual imagery and working memory by analyzing intracerebral EEG recordings from the left inferior temporal lobe of an epileptic patient. Using a set up that allowed real time measurement and visualization of gamma band activity they found a systematic activity increase in the inferior temporal gyrus (ITG) when the patient was visualizing a letter (visual imagery) or during visuo-spatial working memory, but not during perception of letters neither during verbal working memory. In contrast, in the fusiform gyrus (located 7 mm more medially than the ITG), gamma band activity increased during verbal working memory retention and letter presentation, but not during visual imagery or visuo-spatial working memory. From these results the authors conclude that neural networks supporting imagination of visual elements are not necessarily the same as those underlying perception of the element. They also present evidence that gamma band activity in the inferior temporal lobe can be used as direct measure of the efficiency of top down attentional control over visual areas. Finally, the results indicate that only by reading gamma band activity in the ITG and the fusiform gyrus is possible to decode the type of material being maintained in working memory (verbal vs. visuo-spatial) on a single trial basis.

Hamamé, C., Vidal, J., Ossandón, T., Jerbi, K., Dalal, S., Minotti, L., Bertrand, O., Kahane, P., & Lachaux, J. (2012). Reading the mind’s eye: Online detection of visuo-spatial working memory and visual imagery in the inferior temporal lobe NeuroImage, 59 (1), 872-879 DOI: 10.1016/j.neuroimage.2011.07.087

In this study the authors investigated molecular pathways associated with memory formation. They used the behavioral genetics approach to identify genetic variations related to memory performance. An additional fMRI-study was conducted to validate their genetic findings as well as to capture brain activity related to the genotype. Out of 336 healthy subjects that underwent an episodic memory task, 32 were selected for the fMRI-Study due to their comparable memory performance. By choosing subjects of equal memory performance the authors sought to exclude performance dependent brain activation and to capture memory-related genotype effects. The remaining sample of 304 subjects was in a first step genotyped to search for sets of marker loci associated with memory. In a second step using the set association method the previously identified 16 genetic variations were narrowed down to a cluster of seven genetic variations significantly related to memory performance. This cluster was then used to calculate an individual memory-associated genetic score (IMAGS) reflecting the individual memory-related genetic variability. To link the IMAGS to memory associated brain activity activations of the previously selected 32 subjects performing an episodic memory task was measured by fMRI. Results showed that the IMAGS correlated significantly with memory-related brain regions, underlining that the IMAGS captures indeed genetic variations associated with memory. Moreover the authors were able to demonstrate that individual memory performance and memory-related brain activation can directly be associated with a person’s individual genetic variability.

de Quervain, D., & Papassotiropoulos, A. (2006). Identification of a genetic cluster influencing memory performance and hippocampal activity in humans Proceedings of the National Academy of Sciences, 103 (11), 4270-4274 DOI: 10.1073/pnas.0510212103

Posted on behalf of Benjamin Paffhausen:

The authors  studied long term sensitization of the withdrawal reflex in Aplysia, which is an example of
long term memory (LTM). Previous findings suggested that activation of protein kinase A (PKA) and extracellular signal regulated kinase (ERK) lead to long term facilitation (LTF), a form of LTM. PKA and ERK are activated by serotonin.  PKA and ERK both activate an inducer, CREB1 for example, a transcription factor important for LTF. The interesting part is that these two enzymes with the same trigger and the same target need different amounts of time to reach their peak of activity. While PKA is already back to a basal level 15 minutes after activation by serotonin, ERK reaches the peak of its activity after 45 minutes with an initial delay of 25 minutes after serotonin stimulation. So one trial of stimulation would result in very little overlap between these two necessary components for an effect on the inducer.
Before this study, since 1986, the best training protocol (‘standard protocol’) consisted of giving five times a 5-minute serotonin stimulus with a 20-minute interstimulus interval (ISI). The authors developed a computational model of these enzyme cascades to identify an optimized protocol enhancing the effectiveness of training by maximizing the overlap of activated PKA and ERK. They tested the model
on every protocol that only differed in the ISI in a 5 min resolution and an overall time window of 200 minutes. The result of testing every combinations of ISIs on the model was a sequence of ISIs of 10, 10, 5 and 30  minutes, which was predicted to lead to more than 50 % more inducer.  For the protocol which the model predicted (called the ‘enhanced protocol’) the highest overlap of PKA and ERK was tested in vitro against the standard protocol to see if training with that would improve the learning. In neuronal cultures, the activated CREB1 was significantly increased in the enhanced protocol compared to the standard protocol. The magnitude of excitatory postsynaptic potentials after 5 days was greater only in the animals trained with the enhanced protocol. Also the response duration was enhanced, after 1 day in the standard and enhanced protocol, and after 5 days only in the enhanced protocol.

Thus, in what is an exceedingly rare case in biology computational models can predict future results in real biological experiments, in this case enhanced learning and memory.

Zhang, Y., Liu, R., Heberton, G., Smolen, P., Baxter, D., Cleary, L., & Byrne, J. (2011). Computational design of enhanced learning protocols Nature Neuroscience DOI: 10.1038/nn.2990

The authors of the current study (2) investigated the relationship of common genetic variations and gaze patterns. In particular, they tested whether variations in the cannabinoid receptor 1 (CNR1) gene would modulate gaze duration on (happy) faces. To this end, four single-nucleotide polymorphisms (SNPs) in the CNR1 gene were genotyped in 30 healthy subjects (13 male, mean age 24.1 (SD 3.41)),  and associated with gaze duration on dynamic emotional faces, recorded via an 60 Hz eye-tracking system. The SNPs were chosen based on an earlier functional magnetic resonance imaging study (1), which showed that variations in CNR1 modulate striatal response to happy (but not disgust) faces. Results showed that in fact two SNPs (rs806377 and rs806380) in the CNR1 gene were significantly associated with gaze duration on happy (but not disgust) faces. This is not only consistent with their previous study but also extending the previous findings: The allelic group associated with the strongest striatal response in the previous study was associated with the longest gaze duration for happy faces in the current study.

Taken together, the CNR1 seems to play an important role in social reward processing with potential high significance for clinical conditions with deficits in social (reward) processing along with aberrant processing of facial information, such as autism spectrum disorders.

(1) Chakrabarti B, Kent L, Suckling J, Bullmore E, & Baron-Cohen S (2006). Variations in the human cannabinoid receptor (CNR1) gene modulate striatal responses to happy faces. The European journal of neuroscience, 23 (7), 1944-8 PMID: 16623851

(2) Chakrabarti, B., & Baron-Cohen, S. (2011). Variation in the human cannabinoid receptor CNR1 gene modulates gaze duration for happy faces Molecular Autism, 2 (1) DOI: 10.1186/2040-2392-2-10