sfn2006

Li A, Ritter S (2006) Glucoprivation enhances dopamine-beta-hydroxylase gene expression in hindbrain catecholamine cells. Neuroscience 2006 Abstracts 359.12. Society for Neuroscience, Atlanta, GA.

Summary: Hindbrain catecholaminergic neurons are key participants in systemic glucoregulation. Using in situ hybridization, we investigated the effects of glucoprivation on gene expression of dopamine-beta-hydroxylase (DBH), a key enzyme for catecholamines synthesis, to further define the catecholamine subpopulation activated by glucoprivation. Glucoprivation induced by systemic injection of the glycolytic inhibitor, 2-deoxy-D-glucose (2DG, 250 mg/kg body weight) increased total DBH mRNA expression in caudal ventrolateral medullary cell groups (namely, A1, the A1/C1 overlap, and middle C1) from 6 – 49 times control levels. In retrofacial C1, A5 and A7 no enhancement was observed. In the dorsomedial medulla, DBH mRNA hybridization signal was modestly increased (tripled) in cell group A2, but not in the area postrema. Furthermore, a previous hypothalamic microinjection of the retrogradely transported immunotoxin, anti-DBH-saporin, profoundly reduced DBH-positive cells in hindbrain, and abolished the 2DG-stimulated increases of DBH mRNA expression in the caudal ventrolateral medulla and A2 regions. The strong glucoprivation-induced enhancement of DBH gene expression in particular cell populations is consistent with the demonstrated importance of catecholaminergic neurons for glucoregulation and provides further evidence for functional specialization within the catecholamine cell population.

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

Blanco-Centurion CA, Shiromani PJ (2006) Hypocretin-1 stimulates wake and decreases sleep in the basal forebrain of rats with 192-IgG-sap induced lesion of the cholinergic neurons. Neuroscience 2006 Abstracts 458.7. Society for Neuroscience, Atlanta, GA.

Summary: Hypocretin (orexin) containing neurons are located in the lateral hypothalamus (LH) from where they project to major arousal centers in the brain including the basal forebrain (BF). Waking, in part, may be driven by the action of HCRT on BF neurons. However, the BF contains various phenotypes of neurons and to test whether HCRT stimulates wake via the cholinergic neurons we utilize 192-IgG-saporin (192-IgG-SAP) to lesion the BF cholinergic neurons and then determine the potency of HCRT-1 in stimulating wake. Sprague-Dawley rats were administered (under anesthesia) saline (n=5) or 192IgG-SAP (4-6 ug/6ul, n=7). Three weeks later microinjections of aCSF or HCRT (0.06, 0.125, 0.25 nmol/250ul) were administered to the BF via a cannula in a random order. Sleep was recorded for 6h. In lesioned rats 95% of the BF cholinergic neurons were destroyed. However, in these rats, HCRT-1 in a dose-dependent manner significantly increased the time to onset of NREM and REM sleep and this was not different compared to non-lesioned rats. Percent wake was also not different compared to non-lesioned rats. Four hours after microinjection, wake-sleep levels were back to normal. Two studies (Espana et al., 2001) (Thakkar et al., 2001) have infused HCRT-1 into the BF and monitored changes in sleep-wake. However, because the BF contains a heterogenous population of neurons, HCRT-1 is likely to act on all of the BF neurons that contain the HCRT receptor. Here, we found that in the absence of the BF cholinergic neurons HCRT-1 increased wake and decreased sleep to the same degree as in non-lesioned rats, suggesting that non-cholinergic BF neurons are able to mediate unabated HCRT’s arousal signal.

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

Farias P, Valdes J, Riveros M, Torrealba F (2006) The tuberomammillary nucleus is a key component of the arousal system for the appetitive phase of feeding. Neuroscience 2006 Abstracts 361.24. Society for Neuroscience, Atlanta, GA.

Summary: The histaminergic neurons from the tuberomammilary nucleus (TMN) are important in maintaining a high level of arousal or increased sensory alertness. We have seen TMN activation (assessed by Fos-ir) in three different motivated behaviors: feeding, drinking and sexual. The aim of this work is to prove that TMN neurons are essential to promote the arousal during the appetitive phase of feeding. We evaluated the effect of TMN lesion performed with the neurotoxin-saporin coupled to orexin-B on locomotor activity and on thermal responses during food presentation to hungry rats as well as changes in Fos-ir of arousal nuclei and subcortical regions involved in thermal responses. Rats were implanted with telemetric transponders to measure locomotor activity and body core temperature. The brains were processed for Fos-ir, and counterstained with appropriate antibodies to identify ascending arousal system (AAS) nuclei. Histaminergic neurons in the TMN were identified by adenosine deaminase (ADA)-ir. The lesions significantly decreased the number of ADA ir/mm2. The larger lesion (<54% surviving neurons) produced a significant decreased in locomotion and temperature responses to food enticing, compared to intact rats or rats with smaller lesion. Larger lesion abolished the increase in Fos-ir of the AAS nuclei (except the locus coeruleus), and the increase in Fos-ir in thermoregulatory nuclei observed in intact rats. The activation of the orexin neurons of the lateral hypothalamic area and the increase in locomotor activity during food presentation were correlated with the activation of the dorsal TMN. The increased Fos-ir in locus coeruleus and dorsal raphe, and the increase in body core temperature were correlated with the activation of the ventral TMN. In conclusion the TMN neurons seems to act as a “master switch” since they are necessary to initiate the increased arousal that characterizes motivated behaviors, and they likely engage other arousal nuclei as well as thermoregulatory nuclei during the appetitive phase of feeding.

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

Kozak R, Brown HD, Bruno JP, Sarter M (2006) Prefrontal cholinergic modulation of attentional performance-associated increases in posterior parietal acetylcholine release. Neuroscience 2006 Abstracts 369.15. Society for Neuroscience, Atlanta, GA.

Summary: Increases in medial prefrontal cortex (mPFC) cholinergic activity were demonstrated to mediate attentional performance, particularly under conditions that require increases in attentional effort such as coping with the detrimental performance effects of distractors. Activation of the mPFC, in part as a result of cholinergic activity, is thought to orchestrate top-down effects for optimization of input processing elsewhere in the cortex. The cholinergic inputs to posterior cortical regions have been conceptualized as a branch of the PFC efferent circuitry mediating such top-down effects. Therefore, cholinergic inputs to the mPFC are expected to modulate performance-associated activation of cholinergic projections to the posterior parietal cortex (PPC). Furthermore, the mPFC modulatory influence should be particularly robust in response to performance challenges. This hypothesis was tested by assessing attentional performance-associated ACh release in the PPC in rats after removal of cholinergic inputs to the mPFC. Attentional task-performing animals were equipped with a guide cannula for insertion of a microdialysis probe into the PPC. Cholinergic projections to the mPFC and medial cingulate region were lesioned bilaterally by infusing 192-IgG saporin into the mPFC. Standard task performance of intact rats increased PPC ACh release by ~100% (over baseline).While lesioned animals’ standard task performance was mildly but significantly impaired, performance-associated increases in PPC ACh release in lesioned animals were higher than those observed in intact rats (150-200% over baseline). Presentation of the distractor impaired the performance of intact animals; the lesion exaggerated the detrimental effects of the distractor. In both intact and lesion animals, distractor performance-associated increases in PPC ACh release were higher than the increases observed during standard task performance. However, while peak ACh levels were observed immediately after distractor onset in intact rats, PPC ACh release in lesioned animals increased toward the end of the session, peaking 16 min after distractor termination. These data support the hypotheses that mPFC cholinergic inputs contribute to the regulation of PPC cholinergic activity, particularly following performance challenges.

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

Norman GJ, Knox DK, Brothers H, Berntson GG (2006) Nucleus basalis magnocellularis cholinergic lesions attenuate approach and approach-avoidance conflict. Neuroscience 2006 Abstracts 369.17. Society for Neuroscience, Atlanta, GA.

Summary: Approach-avoidance conflict is a construct that underlies many behavioral tests that model anxiety. These tests include the elevated plus maze, shock-probe avoidance, and operant suppression. Previous reports have demonstrated that nucleus basalis magnocellularis (NBM) cholinergic lesions attenuate operant suppression induced by aversive stimuli. Furthermore, NBM cholinergic lesions attenuate avoidance behavior induced by predator odor. This suggests that NBM cholinergic lesions impact avoidance behavior during approach-avoidance conflict but the effect of NBM cholinergic lesions on approach behavior has not been evaluated extensively. In this study we attempted to separately evaluate the effect of NBM cholinergic lesions on approach and approach-avoidance conflict. NBM cholinergic lesions were induced using the selective cholinergic immunotoxin 192 IgG saporin. Time required to start consumption of a food reward was used as an index of approach. Time required to start consumption of a food reward in the presence of predator odor (trimethylthiazoline) was used as an index of approach-avoidance conflict. NBM cholinergic lesions attenuated the time required to consume a food reward in the presence and absence of trimethylthiazoline. The methods in the study describe a novel way of indexing approach-avoidance conflict. Furthermore, the results suggest that NBM cholinergic neurons may separately modulate neurobehavioral systems that mediate approach and avoidance.

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

Howe WM, Burk JA (2006) Effects of cholinotoxic and excitotoxic posterior parietal cortical lesions on attention in rats. Neuroscience 2006 Abstracts 369.18. Society for Neuroscience, Atlanta, GA.

Summary: Basal forebrain corticopetal cholinergic neurons are necessary for normal attentional processing. However, the interactions of acetylcholine with processing mediated by particular cortical regions remain unclear. The posterior parietal cortex has been implicated in models of attention, including the ability to attend selectively to target stimuli when distracting stimuli are presented. In the present experiment, rats were trained to perform a two-lever attention task that required discrimination of visual signals and trials when no signal was presented. Animals then received infusions of the cholinotoxin, 192IgG-saporin, the excitotoxin, n-methyl-D-aspartate, or vehicle into the posterior parietal cortex (n=9/group). Postsurgically, rats were tested for 30 sessions in the same task trained before surgery followed by 30 sessions with the houselight flashed one sec prior to a signal or non-signal. Lesions did not differentially affect performance in the task tested immediately following surgery. However, when the houselight was flashed prior to the signal or non-signal, both lesion groups were differentially affected compared to sham-lesioned animals. Sham-lesioned animals showed a decrease in the latency to press a lever following lever extension when the houselight was flashed compared to sessions when it was not flashed. However, cholinotoxic lesioned animals did not show this effect. Furthermore, planned comparisons revealed an elevated omission rate for excitotoxic lesioned animals compared to sham-lesioned animals during sessions when the houselight was flashed. The present data support the idea that the posterior parietal cortex and its cholinergic afferents from the basal forebrain are necessary for maintaining attentional performance when task irrelevant stimuli are presented.

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

Farovik A, Brown VJ (2006) Basal forebrain cholinergic lesions impair endogenous covert orienting of attention in the rat. Neuroscience 2006 Abstracts 369.19. Society for Neuroscience, Atlanta, GA.

Summary: The cholinergic system plays an important role in attention, including covert orienting of spatial attention. Covert orienting of attention results in faster reaction times and also fewer errors if attention is directed towards target location by a preceding cue compared to when a cue misdirects attention away from the upcoming target location. This differential effect of the cue on performance is called the ‘validity effect’ (Posner, 1980 Q J E P 32:3-25) and it reflects the benefit of directed attention and the cost of needing to redirect attention from one location to another. Covert orienting can be exogenously cued (e.g., a visual event) or endogenously cued (e.g., a ‘cognitive’ cue indicating the probable target location). In the rat, covert orienting has been demonstrated using exogenous cues, but not, to date, endogenous cues. We used a reaction time task to examine the effects of basal forebrain cholinergic lesions on endogenously cued covert attention. Rats made a directional (left or right) response according to the spatial location (left or right) of target. The probable location of the target varied as a function time, such at shorter foreperiods, there was a greater probability of a left target while at longer foreperiods, right targets were more probable. Reaction time was linearly related to the a priori target probability, reflecting directed attention. Eleven rats received bilateral injections of the selective immunotoxin 192-IgG saporin (0.25µg/µl) into the basal forebrain at coordinates AP – 0.7 ML ± 2.9 DV – 6.7 (from dura). Eleven control rats received injections of vehicle. Overall, the lesion did not impair accuracy of performance, however, the reaction times no longer reflected attentional orienting in lesioned animals. Lesioned animals continued to show delay-dependent speeding prior to the target similar to controls, suggesting that changes in reaction times were not due to effects on motor readiness. We conclude that endogenous attentional orienting reflects a different, and independent, process from that of response preparation and that normal cholinergic function is required for the former but not the latter.

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

Brown HD, Kozak R, Sarter M (2006) Bilateral removal of cholinergic inputs to the medial prefrontal cortex disrupts the ability of rats to cope with challenges on attentional performance. Neuroscience 2006 Abstracts 369.20. Society for Neuroscience, Atlanta, GA.

Summary: Studies using microdialysis for the measurement of the release of neurotransmitters in task-performing animals demonstrated attentional performance-associated increases in acetylcholine (ACh) release in the medial prefrontal cortex (mPFC). Moreover, these studies indicated that challenges on attentional performance are associated with augmented increases in mPFC ACh release. Such increases in ACh release were observed while the animals’ performance remained impaired in response to pharmacological or behavioral challenges, and while performance recovered from such challenges. These findings support the general hypothesis that increases in prefrontal cholinergic neurotransmission mediate increases in attentional effort, including the recruitment of prefrontal efferent projections to optimize top-down input processing in sensory and sensory-associational cortical regions. This hypothesis further suggests that cholinergic inputs to these regions directly amplify input processing, and that this more posterior branch of the cortical cholinergic input system is regulated in part by prefrontal outputs (Sarter et al. 2005, 2006). We have previously demonstrated that cortex-wide removal of cholinergic inputs results in persistent impairments in attentional performance. The present experiment was designed to demonstrate that restricted removal of mPFC cholinergic inputs selectively disrupts the animals’ ability to increase their attentional effort in order to maintain and recover from impairments produced by a visual distractor. Animals were trained in a sustained attention task and familiarized with the distractor. Cholinergic inputs to the prelimbic and anterior cingulate cortex were removed by infusions of 192 IgG-saporin into the mPFC. Results indicate that this lesion primarily exaggerated the detrimental performance effects of the distractor. Specifically, the ability of lesioned animals to stabilize their residual hit rate was impaired following distractor presentation. These results indicate that the integrity of cholinergic inputs to the mPFC is necessary for the recruitment of the cognitive mechanisms mediating stabilization and recovery of cognitive performance following attentional challenges.

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

Newman LA (2006) Comparison of the effects of selective cholinergic or noradrenergic deafferentation in the medial, prefrontal cortex on sustained attention. Neuroscience 2006 Abstracts 369.21. Society for Neuroscience, Atlanta, GA.

Summary: Acetylcholine (ACH) and norepinephrine (NE) have been shown to be critically important in controlling the activity of cortical neurons during attention demanding tasks. ACH efflux increases during performance of a sustained attention task and the introduction of distracting stimuli augment this efflux (Himmelheber, Sarter and Bruno 2000). Electrophysiological recordings in NE cell bodies in the locus coeruleus show an increase in tonic firing when distracting stimuli are presented during an attentional task (Aston-Jones and Cohen 2005). The current study assesses the effects of neuroanatomically discrete depletions of these neurotransmitters in the prefrontal cortex (PFC) on a sustained attention task. Male, Long Evans rats received either sham (SHAM), cholinergic (ACH LX) or noradrenergic (NE LX) lesions of the medial wall of the PFC by injections of vehicle, 192 IgG saporin or dopamine beta-hydroxylase saporin respectively. Rats were trained to detect brief, temporally unpredictable, visual cues of varying duration (500, 100, 25 msec) and discriminate these events from non-signal trials. Several manipulations were run to vary the attentional load of the task. These manipulations include a tone with a predictable on-off pattern or a tone with an unpredictable on-off pattern. Preliminary results suggest that NE LX rats were more vulnerable than SHAM or ACH LX rats to the detrimental effects of the unpredictable but not predictable tone. These data suggest that NE is critical to filtering unpredictable distractor stimuli. Additionally we tested the effects of disrupting the temporal contiguity between correct responses and reinforcement as this has previously been shown to increase NE efflux in the frontal cortex. All animals were impaired by the introduction of a variable delay between a correct response and the delivery of a food reinforcer, however NE and ACH lesions of the PFC augmented this impairment. This suggests that both neuromodulators are critical in maintaining performance when reinforcer predictability changes. Manipulations of event rate, event asynchrony, signal probability and the dynamic stimulus range will also be discussed.

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

Pasumarthi RK, Fadel J (2006) Anatomical and neurochemical mediators of nicotine-induced activation of orexin neurons. Neuroscience 2006 Abstracts 369.22. Society for Neuroscience, Atlanta, GA.

Summary: Orexin/hypocretin neurons of the lateral hypothalamus and contiguous perifornical area (LH/PFA) are important for state-dependent behavior and metabolic regulation. These neurons are activated-as indicated by Fos expression-by a variety of psychostimulant drugs including nicotine. Previously, we have shown that acute nicotine-induced activation of orexin neurons can be blocked by either the non-selective nicotinic antagonist mecamylamine or the selective α4β2 antagonist dihydro-beta-erythroidine (DHβE). However, the hypothalamic afferents and neurotransmitters mediating nicotine-elicited activation of orexin neurons remain to be established. Since the LH/PFA is rich in glutamatergic and cholinergic inputs, we performed in vivo microdialysis to determine the effect of both systemic and local nicotine on release of glutamate and acetylcholine (ACh) in this region of the hypothalamus. Local nicotine administration (100 μM; 2.0 mM) increased ACh and glutamate release in the LH/PFA. Furthermore, in a separate experiment, nicotine-elicited Fos expression in orexin neurons was reduced by either ibotenic acid lesions of the prefrontal cortex (PFC), which provides a substantial glutamatergic input to the hypothalamus, or by cholino-selective (192 IgG saporin) lesions of the basal forebrain. Collectively, these data suggest that glutamatergic inputs from the PFC and cholinergic inputs from the basal forebrain may act cooperatively to mediate the effect of acute nicotine on orexin neurons. Neural circuitry linking orexin neurons with the basal forebrain, PFC and PVT is likely to contribute to the effects of nicotine on wakefulness and attention.

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