TL neuro

November 11, 2011

SfN Poster Priorities (11/12/11)

Filed under: Uncategorized — vapharmboy @ 8:31 pm

There are several posters that I don’t want to miss during the first day of SfN 2011. First up, a series of posters on learning and memory, especially associative memory. These are obviously of interest because of our current associative memory projects with the monkeys 

1)

Program#/Poster#:        97.07/WW22

Presentation Title:         Posterior cingulate cortex is critical for associative learning

Presentation Time:       Saturday, Nov 12, 2011,3:00 PM – 4:00 PM

Abstract:                      Anatomical and neurophysiological evidence suggest a role for posterior cingulate cortex (CGp) in learning and memory. CGp is situated at the intersection of brain systems involved in visual orienting, emotional processing, and memory, indicated by its connections to parietal cortex, orbitofrontal and anterior cingulate cortex, and the medial temporal lobe (MTL), respectively. Moreover, CGp hypometabolism is closely linked to early cognitive deficits in Alzheimer’s Disease. Despite this evidence, the precise contributions of CGp to learning and memory remain unclear. Some models posit a role for CGp in associative learning, others proffer a more prominent role in valuation, while still others focus on a role for CGp in long-term memory.
To distinguish amongst these possibilities, we studied the relationship of neuronal activity in CGp to learning and memory in monkeys performing a variant of the location-scene association paradigm. On each trial, monkeys saw a neutral scene photograph, then shifted gaze to one of two targets for liquid reinforcement. The correct target for each scene initially had to be learned by trial and error, and subsequently recovered from long-term memory to sustain performance. We included both highly familiar reference scenes and scenes novel for each session, as well as both high and low value scenes.
After monkeys had learned the basic task, we recorded the activity of single CGp neurons and then, in separate sessions, reversibly inactivated tissue in this region with muscimol. Firing rates of single CGp neurons were modulated during the task in ways relevant to learning. Most CGp neurons showed a prominent error signal following incorrect choices. This error signal was larger for new scenes than for previously learned reference scenes. CGp firing rates over the course of the session tracked global learning rate. Finally, muscimol injections significantly impaired learning, but performance on previously-learned scenes was unaffected. Notably, learning of high-value scenes was also unaffected during muscimol inactivation. These results provide strong evidence that CGp functionally contributes to associative learning but not to the storage or retrieval of information from long-term memory.

2)

Program#/Poster#:        99.15/WW66

Presentation Title:         Mitigated effects of methylphenidate on visual working memory in the macaque monkey

Presentation time:         Saturday, Nov 12, 2011,3:00 PM – 4:00 PM

Abstract:          Catecholamine neurotransmission has been implicated as a critical factor in the operation of numerous cognitive functions, including working memory (WM). The psychostimulant drug methylphenidate (MPH) – commonly used to treat Attention Deficit Hyperactivity Disorder and potentially a drug with cognitive enhancing capabilities – has been shown to produce dose-dependent changes in WM performance in both humans and animals, via combined actions at dopamine D1 and noradrenergic α2 receptors. In general, the dose-dependency of these effects conforms to an “inverted U” function, with optimal doses leading to performance enhancements, and doses above and below this level producing minimal effects or performance decrements. Most studies investigating the effects of MPH on WM in animals have employed delayed-response tasks requiring the retention of a single memorandum. Consequently, little is known of the effects of MPH on WM at higher memory loads. Characterization of the effects of MPH across the range of operation of WM is critical to fully establish the link between catecholamine transmission and changes in WM performance. To address this, we employed a psychophysical approach in which WM performance was evaluated over a range of loads and MPH doses. Female rhesus macaque monkeys performed a sequential comparison task which required them to identify the location of a color change within an array of 2 to 5 colored squares following a retention interval (Heyselaar et al., 2011). We compared the proportion of correct responses and response latencies between sessions in which MPH (0.5 – 9.0 mg/kg) was orally administered, and control sessions in which no drug was given. We predicted that MPH would affect WM performance in a dose-dependent manner, with optimal doses leading to an increased proportion of correct responses and shorter response latencies relative to control sessions, and doses above or below this level producing either no or opposite effects. We further reasoned that such effects would scale with memory load due to the increased demands on WM resources at higher loads. Contrary to these predictions, no effects of MPH on the proportion of correct responses were observed at any WM load at any of the doses tested. MPH produced variable effects on response latencies, with the most consistent observation being a general increase at higher doses. These data suggest that the effects of MPH on WM performance are limited, regardless of memory load.

3)

Program#/Poster#:        100.03/XX6

Presentation Title:         NAcc neurons’ inhibition during reversal learning: A pharmacological and an optogenetic approach.

Presentation time:         Saturday, Nov 12, 2011,3:00 PM – 4:00 PM

Abstract:                      Purpose: The aim of this study was to understand the contribution of NAcc cells in reversal learning performance by using two approaches. First, inhibition of NAcc cells using a Gaba-a agonist (Muscimol). Second, inhibition of NAcc cells using light-sensitive opsins (halorhodopsin). The prediction from this investigation was that neuronal suppression of NAcc neurons would have a greater impact on reversal learning performance in a within-session reversal than in a between session. Methods: Rats (Muscimol group) (n=10) were implanted with bilateral guide cannulae above the NAcc. Another group of rats (n=6) received injections of lentivirus (halorhodopsin) in the NAcc, and were implanted with a fiber guide system that would deliver a yellow light to target neurons via an optical fiber. After surgery, rats were trained to complete an FR1 discrimination, and then tested in a between reversal and a within session reversal task. Results: NAcc implanted rats that received muscimol injections made significantly fewer errors during the between reversal session than the control group (saline, n=5): F (1, 9)=42.885, p<0.001. NAcc rats also took significantly longer than the control group to reach criterion: F(1,9)=4.933, p<0.05. However, NAcc rats made significantly more errors than the control group during the more complex within session reversal F(1,9)=7.031,p<0.05. Conclusion: Our preliminary results suggest that NAcc neurons play an instrumental role in reversal learning performance, especially when task complexity increases. Using optogenetics, we will be able to more precisely define what the function of NAcc neurons during reversal performance is (1:before bar pressing, 2: when an error is made, or 3: between choosing the right lever and collecting reward).

Then, there a few cannabinoid-related posters that I’ve got to see.

1)

Program#/Poster#:        38.08/D21

Presentation Title:         Both dglα and dglβ regulate the production of 2-arachidonoyl glycerol in autaptic hippocampal neurons

Presentation time:         Saturday, Nov 12, 2011,4:00 PM – 5:00 PM

Abstract:                      Cannabinoids are part of an endogenous signaling system consisting of cannabinoid receptors and endogenous cannabinoids (eCBs) as well as the enzymatic machinery to produce and break down these eCBs. Depolarization-induced suppression of excitation (DSE) is a form of cannabinoid CB1 receptor-mediated inhibition of synaptic transmission that involves the production of the eCB 2-arachidonoyl glycerol (2-AG). The role of diacylglycerol lipase (DGL) in the formation of 2-AG during depolarization is controversial: hippocampal DSI is absent in DGLα knockout mice, yet DGL inhibitors do not always block DSI. Furthermore, the two isoforms of DGL, DGLα and DGLβ are impossible to distinguish by available pharmacological tools. Of these DGLα has received considerable attention in 2-AG production. What role, if any, might be played by DGLβ remains largely unexplored. Autaptic hippocampal neurons are well-suited to a comparative study of the roles of these enzymes in mediating the robust endogenous DSE present in these cultured neurons under controlled conditions.
To investigate the importance of DGLα and DGLβ for 2-AG production in DSE we developed siRNA constructs for each enzyme. We found that our constructs reduced expression of these proteins by 70% and 72% in DGLα- and DGLβ-expressing HEK293 cells, respectively. We then used these constructs to knockdown DGL expression in autaptic hippocampal neurons.
We find that knockdown of DGLα results in a substantial reduction of DSE, shifting the ‘depolarization response curve’ from an EC50 value of 1.6 sec to 6.4 sec (non-overlapping 95% confidence intervals). Interestingly, DGLβ diminishes DSE as much or more (EC50 54.8 sec, non-overlapping CI), suggesting that DGLβ is responsible for a portion of 2-AG production in autaptic neurons. In separate experiments we confirmed that siRNA for each DGL did not reduce the expression of the other DGL in HEK293 cells.
We conclude that both DGLα and DGLβ play a role in endogenous cannabinoid modulation of synaptic transmission. Our results identify DGLβ as a new potential target for modulation of the cannabinoid signaling system.

2)

Program#/Poster#:        91.08/VV4

Presentation Title:         Executive function, the endocannabinoid system and the default mode network

Presentation time:         Saturday, Nov 12, 2011,4:00 PM – 5:00 PM

Abstract:                      Introduction. The term executive function describes a set of high level cognitive functions that are essential for goal directed behavior, such as the ability to monitor, change and plan behavior as needed. Behavioral studies suggest involvement of the endocannabinoid (eCB) system in executive function [1]. The eCB system acts as a neuromodulatory system through regulation of both excitatory and inhibitory neurotransmission [2]. We used fMRI to investigate eCB involvement in executive function, by measuring the effect of eCB perturbation on task performance, task activity, including default mode network (DMN) activity.
Methods. A pharmacological MRI study was conducted with a placebo-controlled, cross-over design, investigating the effect of the eCB agonist Δ9-tetrahydrocannabinol (THC) on brain function. 20 healthy volunteers performed a continuous performance task with identical pairs [3]. Brains scans were acquired using a Philips Achieva 3.0 T scanner (TR 22.5 ms; TE 33.2 ms; flip angle = 10°; FOV 224×256×160; matrix 56× 64×40; scan time 0.6075 s; 40 slices (sagittal orientation)). Effects of eCB were measured in a set of activated as well as deactivated regions.
Results. After THC administration subjects showed, among other effects, an increase in VAS score of ‘feeling high’ (F(1,19) = 19.10, p < 0.001), and reduced ‘alertness’ (F(1,19) = 9.24; p = 0.007). Task performance was impaired after THC administration, (t = 2.93; p= 0.008). This was associated with elevated activity in the set of deactivated brain regions (F = 13.20; p < 0.002), including posterior cingulate gyrus and angular gyrus. In addition, activity in this network was negatively correlated with task performance after THC administration (r = -0.43, p = 0.03). Positively activated regions, notably prefrontal and parietal cortex, did not show any effects of THC (F = 0.004; p = 0.95).
Conclusion. THC administration caused impairment in task performance as well as reduced deactivation in a set of brain regions that have been linked to the DMN, while regions that were activated by the task were unaffected. These results suggest involvement of the eCB system in regulation of DMN activity, and indicates that executive function can be negatively impacted by a challenged eCB system, through insufficient deactivation of the DMN. Results point to the possibility of involvement of the eCB system in impaired executive function, as found in psychiatric or neurological disorders.

3)

Program#/Poster#:        102.09/XX52

Presentation Title:         Epigenetic modulation of endocannabinoid-dependent extinction of fear memories

Presentation time:         Saturday, Nov 12, 2011,1:00 PM – 2:00 PM

Abstract:                      Treatment of post-traumatic stress disorder, phobias, and panic disorder often rely upon progressive extinction of fear memories, where the fear-inducing stimulus is presented repeatedly without negative consequence. Previous reports indicate that that the endocannabinoid system is essential for the extinction of learned fear. Global genetic deletion of the cannabinoid 1 receptor (Cb1) in a mouse model system blocks extinction learning. Administration of a Cb1 antagonist in wild-type mice prior to extinction learning similarly blocks extinction learning (Marsicano 2002). Additionally, Barad and colleagues demonstrated that broad, non-specific HDAC inhibition enhances emotional learning and extinction of conditioned fear (Bredy et al., 2007; Bredy and Barad, 2008). We have several goals: 1) if extinction learning can be blocked with administration of a Cb1 antagonist, we predict that we can enhance extinction with a compound that augments endogenous cannabinoid tone, and 2) if extinction learning can be enhanced with a broad, non-specific HDAC inhibitor, we propose that a relatively specific HDAC inhibitor, RGFP963, will also augment extinction of conditioned fear.
To test this hypothesis, fear conditioned mice were systemically infused with URB597, the fatty acid amide hydrolase inhibitor, and/or RGFP963 during fear extinction training. We have found URB597 enhances within-session extinction compared to vehicle (p<.05) and RGFP963 enhances extinction retention. We are additionally examining whether approaches that enhance within-session extinction (URB597) and those that enhance consolidation of extinction (RGFP963) are complementary and thus potentially additive in their overall effects. These data suggest that HDAC inhibitors and compounds modulating the endocannabinoid system effectively enhance the extinction of fearful memories, and may provide further understanding of mechanisms and potential drug targets that may enhance behavioral therapy treatment of fear and anxiety/panic-related disorders.

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