sfn2008

Croxson PL, Browning PGF, Gaffan D, Baxter MG (2008) Cholinergic depletion of the inferior temporal cortex interferes with recovery from episodic memory deficits. Neuroscience 2008 Abstracts 292.7/SS20. Society for Neuroscience, Washington, DC.

Summary: Cholinergic innervation of the temporal lobe has been suggested to have a role in episodic memory, a function which is also disrupted by lesions or disconnections of the medial temporal lobe circuit. Acetylcholine may be necessary for the specific function of some brain regions. Alternatively, it may be necessary for cortical plasticity and remodeling in those conditions in which the animal has to adapt following new task demands or injury. To investigate the role of cholinergic projections to inferotemporal cortex in episodic memory, and how loss of these projections might interact with damage to other brain structures necessary for normal memory function, we trained monkeys preoperatively on object-in-place scene discrimination problems until they could rapidly learn many problems within a testing session. Because learning occurs rapidly, mostly in a single trial, and depends on the presentation of discrimination problems in unique background scenes, this task models key features of human episodic memory. For the first stage of the experiment, the monkeys then received either a fornix transection or mammillary body ablation, both of which are known to impair learning in this task. All of the monkeys were impaired at scene learning after fornix or mammillary body lesions compared to their preoperative performance, consistent with previous results. In the second stage of the experiment, the monkeys underwent a second surgery in which we used the immunotoxin ME20.4-saporin to selectively deplete cholinergic inputs to the inferotemporal cortex. We then re-tested the monkeys on scene learning, and they were no more impaired than they were after their first surgery. This result is in striking contrast to an earlier finding by our laboratory that the effect of fornix transection is greatly exacerbated by prior depletion of acetylcholine from inferotemporal cortex (Browning et al. 2008, in press). The key difference between these two experiments is the order in which the lesions were placed: cholinergic depletion of inferotemporal cortex before fornix transection results in severe amnesia, whereas severe amnesia does not occur if the lesions are sustained in the opposite order. This finding suggests that monkeys require acetylcholine in inferotemporal cortex in order to adjust to the effects of a fornix lesion on episodic memory. This is consistent with a role for cholinergic input to neocortex in cortical plasticity and remodelling, rather than a specific role in certain brain functions such as episodic memory.

Related Products: ME20.4-SAP (Cat. #IT-15)

Baxter MG, Kyriazis DA, Croxson PL (2008) Cholinergic depletion of prefrontal cortex impairs acquisition of the delayed response task in rhesus monkeys. Neuroscience 2008 Abstracts 292.9/SS22. Society for Neuroscience, Washington, DC.

Summary: The involvement of corticopetal cholinergic projections in cognition remains difficult to define. Some investigators have suggested that normal cortical function requires an intact cholinergic input, whereas others emphasize a selective role of acetylcholine in attentional function or plasticity. Because of the anatomical and functional homology of human and macaque cortical structures, studies of the effects of selective ablation of cholinergic projections to cortical regions in the macaque would clarify the functions for which these projections are essential. We have tested 3 male rhesus monkeys with multiple bilateral injections of the immunotoxin ME20.4-saporin into lateral and orbital prefrontal cortex on a suite of cognitive tasks dependent on the integrity of orbital and ventrolateral prefrontal cortex, on which they were unimpaired. These tasks included new object-in-place scene learning, strategy implementation, and reinforcer devaluation. To determine the involvement of acetylcholine in dorsolateral prefrontal cortex function, we then trained these monkeys on the spatial delayed response task (Goldman, 1970; Bachevalier and Mishkin, 1986) in a manual testing apparatus. In this task the monkey watches as an experimenter places a small food reward in one of two wells of a test tray and then covers both wells with identical gray plaques. After a brief delay (1-5 sec) during which an opaque screen is interposed between the monkey and experimenter, the monkey is allowed to obtain the reward by displacing the plaque covering the well that was baited by the experimenter. Thus, the monkey must maintain the baited location (left or right) in memory during the brief delay interval in order to choose correctly. Performance of this task is devastated by ablation of dorsolateral prefrontal cortex. The monkeys with cholinergic depletion of lateral and orbital prefrontal cortex were also unable to learn the task to criterion, which four unoperated control monkeys learned readily. This finding suggests that acetylcholine, although not critical for functions of ventrolateral and orbital prefrontal cortex, is essential for dorsolateral prefrontal cortex function. An alternative explanation, which we are currently investigating, is that acetylcholine is necessary for the prefrontal cortex to adapt to the different task demands of delayed response, relative to the tests of discrimination learning with which these monkeys had extensive experience. This would be consistent with a role for cholinergic input to neocortex in cortical plasticity and remodeling.

Related Products: ME20.4-SAP (Cat. #IT-15)

Di Sebastiano AR, Yong-yow S, Coolen LM (2008) The role of orexin in sexual behavior and sexual reward of the male rat. Neuroscience 2008 Abstracts 97.4/UU18. Society for Neuroscience, Washington, DC.

Summary: The hypothalamic neuropeptide orexin has been demonstrated to play a role in reward related to drugs of abuse and is potentially involved in regulation of natural rewarding behaviors. Male sexual behavior has been shown to activate orexin neurons and this behavior is altered by administration of orexin receptor agonists or antagonists. However, the exact role of orexin in male sexual performance, sexual motivation and reward is currently unclear. Therefore, the goal of the current study was to test the hypothesis that orexin plays a critical role in sexual behavior, motivation and reward. First, using Fos as a marker for neural activation, we investigated activation of orexin neurons following different parameters of sexual behavior in sexually naïve and experienced male rats. It was demonstrated that orexin neurons in the lateral hypothalamic area (LHA) and in the dorsal medial hypothalamus/perifornical (PFA-DMH) region become activated with presentation of the female and there is no further increase in activation with other components of mating (15-30% in LHA; 65-80% in PFA-DMH). Next, we tested the functional role of orexin utilizing orexin-cell body specific lesions. Adult male rats underwent lesion or sham surgery using the targeted toxin orexin-saporin or blank-saporin respectively. Following two weeks recovery, sexual behavior was recorded over the course of four mating trials. During the first mating trial, males with complete lesions showed significantly shorter latencies to mount and intromit. This suggests that lesions facilitated sexual performance in naïve animals. This facilitation was attenuated by sexual experience as lesions did not affect any parameter of sexual behavior in experienced animals. Next, runway tests were conducted to determine motivation to run towards a potential partner over two conditioning trials. Lesions did not alter sexual motivation, as lesion and sham males all demonstrated increased speed to run towards an estrous female during the second trial. Finally, a conditioned place preference (CPP) paradigm was conducted as a measure of sexual reward. All groups formed a conditioned preference for the mating-paired chamber, indicating that lesions did not significantly disrupt sexual reward. Overall, these findings suggest that orexin does not play a critical role in male sexual performance, motivation, and reward, however may be involved in general arousal related to sexual behavior.

Related Products: Orexin-B-SAP (Cat. #IT-20), Blank-SAP (Cat. #IT-21)

Emanuel AJ, Dinh TT, Ritter S (2008) The ablation of hindbrain catecholamine neurons innervating medial hypothalamic nuclei abolishes glucoprivic feeding, but spares the orexigenic response to ghrelin. Neuroscience 2008 Abstracts 85.2/RR15. Society for Neuroscience, Washington, DC.

Summary: Ghrelin is an orexigenic peptide synthesized in the stomach and secreted during fasting. Receptors for ghrelin are present in the brain and direct injection of ghrelin into the brain evokes feeding. Nevertheless, Y. Date et. al. (2002) have claimed that gastric vagal afferent neurons are the major pathway conveying ghrelin’s signals for starvation and growth hormone secretion to the brain. Furthermore, this group (Date et. al., 2006), has reported that noradrenergic neurons transmit ghrelin’s orexigenic signals from the hindbrain to the hypothalamus. The latter assertion was based on the loss of ghrelin-induced feeding in rats injected into the arcuate nucleus (ARC) with anti-dopamine beta hydroxylase (DBH) conjugated to saporin (DSAP), which retrogradely destroys DBH-containing neurons. We previously showed that DSAP microinjection either into the hypothalamic paraventricular nucleus (PVH) or ARC abolished glucoprivic feeding. Since glucoregulatory responses include alterations of both feeding and growth hormone secretion, we reasoned that the same catecholamine neurons sensitive to glucoprivation may contribute to these responses following ghrelin. To investigate this issue further, we microinjected DSAP (n=7) or unconjugated saporin (SAP control, n=7) bilaterally into the PVH of Sprague-Dawley rats (approximately 400 g BW). Three weeks later, daytime tests for feeding responses to 2-deoxyglucose (2DG, 200 mg/kg, 4-hr test) and ghrelin (15 µg/kg, i.p., 2-hr test) were conducted. As expected, DSAP abolished 2DG-induced feeding. However, the response to ghrelin was not abolished in DSAP treated rats. In fact, feeding in response to ghrelin was significantly enhanced in DSAP-treated rats, compared to the control SAP group (p<0.05). These results confirm our prior findings relative to the role of catecholamine projections in glucoprivic responses, but they contradict the results previously reported by Date et. al. The difference between our injection sites (we injected DSAP into the PVH, and Date injected into the ARC) is not likely to account for the different results since injections of DSAP into either site eliminate DBH terminals throughout the medial hypothalamus and appear to lesion the same population of catecholamine neurons. Therefore, until more detailed analysis is conducted, we conclude that hindbrain catecholamine neurons are required for glucoprivic but not ghrelin-induced feeding.

Related Products: Anti-DBH-SAP (Cat. #IT-03)

Pang K, Janke K, Servatius RJ (2008) Role of medial septum-diagonal band of Broca neurons in cognitive flexibility. Neuroscience 2008 Abstracts 89.20/SS37. Society for Neuroscience, Washington, DC.

Summary: Cholinergic and GABAergic neurons are major components of the septohippocampal pathway, and comparisons between the two neuronal populations are important for understanding the function of medial septum and vertical limb of the diagonal band (MSDB). Recently, we have been investigating the importance of MSDB neurons in cognitive flexibility. Cognitive flexibility is commonly examined in procedures that require reversal of stimulus-reward associations and those that require shifts in attention set, involving switching attention to different stimulus dimensions. Our recent studies demonstrated that selective damage of GABAergic but not cholinergic MSDB neurons impaired spatial reversal. The present study will determine whether selective lesions of cholinergic or GABAergic MSDB neurons impairs shifting of attentional set. Sprague Dawley rats will be administered saline, GAT1-saporin or 192-IgG saporin into the MSDB to produce no damage, selective GABAergic damage or selective cholinergic damage, respectively. Verification of the lesions will be performed using immunocytochemistry at the end of the study. The behavioral procedure will occur in a plus maze. Rats will start in one of two arms opposite each other (i.e., north and south arms) randomized across trials. On any single trial, the arm opposite the starting arm will be blocked forming a T-maze. Rats will have a choice of entering one of the remaining 2 arms (east or west arms) for food reinforcement. Half of the rats will be reinforced to make an egocentric response (left or right turn) and the other rats will be reinforced to go to a particular arm (east or west; allocentric response) regardless of starting location. After reaching criterion (10 consecutive correct choices), the goal location will be reversed (i.e., left turn to right turn or east to west arm) or shifted to a different dimension (i.e., left turn to east arm or west arm to right turn). It is expected that rats treated with GAT1-saporin, but not 192-saporin, will be impaired on the reversal procedure, similar to previous studies. Impairments in shifting attention set would suggest a global impairment in cognitive flexibility. However, an impairment in the reversal procedure but not shifting of attention set would be similar to recently described deficits in the nucleus basalis magnocellularis using ibotenic acid and 192-IgG saporin lesions (Tait and Brown, Behav Brain Res. 187:100, 2008). The results of this study will provide important insight into the role of the MSDB in learning, attention and cognitive flexibility.

Related Products: 192-IgG-SAP (Cat. #IT-01), GAT1-SAP (Cat. #IT-32)

Wallace DG, Winter SS, Martin MM, Mcmillin JL (2008) 192-IgG Saporin lesions of the medial septum or nucleus basalis magnocellularis disrupt exploratory trip organization. Neuroscience 2008 Abstracts 90.15/SS57. Society for Neuroscience, Washington, DC.

Summary: Previous work has demonstrated that rats use self-movement cues to organize their exploratory behavior. The hippocampus and several cortical areas have been implicated in processing self-movement cues. The current study investigated whether selective cholinergic deafferentation of the hippocampus or cortex differentially influenced the organization of exploratory behavior. Long Evans female rats received injections of 192 IgG-Saporin or saline into the medial septum (MS) or nucleus basalis magnocellularis (NB). Subsequent to recovery, rats were placed on a large circular table that provided access to a refuge under complete dark conditions (infrared cameras and goggles were used to visualize the rat). All rats established a home base in the refuge; however, impairments in exploratory trip organization specific to the homeward segment were observed in MS and NB rats. Both groups displayed increased variability in the temporal pacing of speeds on the homeward return, consistent with impaired distance estimation. Only the NB group displayed a significant reduction in stop duration after short, medium, and long searching progressions. These observations are consistent with different roles for hippocampal and cortical cholinergic function in processing self-movement cues.

Related Products: 192-IgG-SAP (Cat. #IT-01)