sfn2006

Torner EK, Flesher MM, Chavez CM, Linton KD, Herbert MS, Butt AE (2006) 192 IgG-saporin lesions of the cholinergic basal forebrain disrupt attention and awareness in Pavlovian trace but not delay conditioning in rats. Neuroscience 2006 Abstracts 667.19. Society for Neuroscience, Atlanta, GA.

Summary: Recent research suggests that Pavlovian trace conditioning, but not delay conditioning, requires awareness or attention, where these processes appear to depend on specific brain systems. For example, past research has shown that although amnesiac humans with damage to the hippocampus (HPC) acquire a normal conditioned response (CR) in delay conditioning paradigms where the conditioned stimulus (CS) and unconditioned stimulus (US) partly overlap, they fail to acquire the CR in trace conditioning paradigms where the CS and US are separated in time. Others have shown that the anterior cingulate cortex (ACC) is similarly necessary for trace but not delay conditioning in rats. Another study in rabbits also suggests medial prefrontal cortex (mPFC) involvement in trace but not delay conditioning. The basal forebrain cholinergic system (BFCS) has projections to mPFC, ACC, and HPC. Given that each of these regions is critical for trace but not delay conditioning, we hypothesized that lesions of the BFCS using 192 IgG-saporin (SAP) would selectively impair trace but not delay appetitive conditioning in rats. Rats received bilateral injections of SAP or saline only (sham lesion control group) into BFCS prior to conditioning with a white noise CS and sucrose pellet US in either a delay or 10 s trace conditioning paradigm. Results supported our hypotheses, with the BFCS lesion group showing normal delay conditioning but impaired trace conditioning. In order to assess the potential for distraction to exacerbate the observed BFCS lesion-induced impairments in trace conditioning, a visual distracter (continuously flashing light) was added to the trace conditioning paradigm in a second experiment. Given evidence suggesting BFCS involvement in attention, it was hypothesized that the addition of a visual distracter to the trace conditioning task would cause a greater degree of impairment in the BFCS lesion group than in the control group tested in that task. Preliminary data support this hypothesis. Together, these experiments suggest that the BFCS is necessary for normal trace conditioning, which is argued to require both awareness and working memory. The additional impairment in trace conditioning caused by the visual distracter further suggests a role for the BFCS in mediating attention.

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

Van Kampen JM, Eckman CB (2006) Cholinergic agonists restore deficits in hippocampal neurogenesis after basal forebrain lesions in the adult rat brain. Neuroscience 2006 Abstracts 674.13. Society for Neuroscience, Atlanta, GA.

Summary: Discrete regions of the adult CNS, including the dentate gyrus of the hippocampus, retain the capacity for neurogenesis. Progenitor cells in these regions may represent a potential source of endogenous cells for replacement therapies in neurodegenerative diseases. In order to facilitate the development of such therapeutic approaches, an understanding of the microenvironmental signals regulating neurogenesis in the adult brain is essential. Small molecule neurotransmitters, such as acetylcholine, have been shown to regulate neurogenesis both during development and in the adult brain. In the studies presented here, we examine the effects of various cholinergic agonists on hippocampal neurogenesis in the adult rat brain. Intraventricular administration of a nicotinic agonist significantly attenuated proliferation, while muscarinic agonists triggered a dose-dependent increase in neurogenesis within the dentate gyrus and CA1 regions of the hippocampus. This effect was blocked by the M1 receptor-selective antagonist, pirenzepine. The basal forebrain provides an abundant source of cholinergic input to the hippocampus, thought to play an important role in learning and memory and Alzheimer’s disease (AD) pathophysiology. Loss of this cholinergic innervation, as occurs in AD, was achieved by a selective immunotoxin and resulted in a significant reduction in hippocampal neurogenesis. This loss of neurogenesis was reversed by intraventricular administration of a muscarinic receptor agonist. The loss of basal forebrain cholinergic inputs observed in AD may contribute to deficits in learning and memory through reductions in hippocampal neurogenesis. The results reported here suggest that pharmacological manipulation of the cholinergic system may represent a means of stimulating hippocampal neurogenesis as a potential treatment strategy.

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

Sengelaub DR, Osborne MC, Little CM, Huyck KD, Verhovshek T (2006) Neuroprotective effects of testosterone in two models of spinal motoneuron injury. Neuroscience 2006 Abstracts 683.12. Society for Neuroscience, Atlanta, GA.

Summary: Following induced death or axotomy of spinal motoneurons remaining motoneurons atrophy, but this atrophy can be reversed or prevented by treatment with testosterone (T). For example, partial depletion of motoneurons from the highly androgen-sensitive spinal nucleus of the bulbocavernosus (SNB) induces dendritic atrophy in remaining motoneurons, and this atrophy is prevented by treatment with T. To test whether T has similar effects in more typical motoneurons, we examined potential neuroprotective effects in motoneurons innervating muscles of the quadriceps. Motoneurons innervating the vastus medialis muscle were selectively killed by intramuscular injection of cholera toxin conjugated saporin. Simultaneously, some saporin-injected rats were given implants containing T or left untreated. Four weeks later, motoneurons innervating the ipsilateral vastus lateralis muscle were labeled with cholera toxin conjugated HRP, and dendritic arbors were reconstructed in 3 dimensions. Compared to intact control males, partial motoneuron depletion resulted in decreased dendritic length (70%) and soma size (13%) in remaining quadriceps motoneurons, but as in the SNB, this atrophy was attenuated by T treatment. In a second model, brain-derived neurotrophic factor (BDNF) and T have a combinatorial effect in the maintenance of motoneurons after axotomy in that dendritic morphology is supported by BDNF treatment, but only in the presence of T. Using immunohistochemical methods, we examined the regulation of the expression of the BDNF receptor, trkB, by T. In both the highly androgen-sensitive motoneurons of the SNB and the more typical quadriceps motoneurons, the expression of trkB receptors was regulated by the presence of T. Motoneurons of castrated animals deprived of T show reduced expression of trkB receptors compared to motoneurons of intact animals or castrated animals given T replacement. This finding suggests that maintenance of trkB receptors with T may be necessary to permit the trophic effects of BDNF in supporting dendritic morphology after axotomy. Together, these findings suggest that T regulates neuroprotective effects through a variety of mechanisms, not only in highly androgen-sensitive motoneurons, but in more typical motoneuron populations as well.

Related Products: CTB-SAP (Cat. #IT-14)

Vaucher EJ, Dotigny F (2006) Cell type specificity of the c-Fos immunoreactive neurons of cortical layer IV after patterned visual stimulation. Neuroscience 2006 Abstracts 545.28. Society for Neuroscience, Atlanta, GA.

Summary: The cortical processing of specific visual stimuli may be enhanced or suppressed by neuromodulators, such as acetylcholine or norepinephrine as early as in the primary visual area. We have recently shown using c-Fos immunoreactivity that the specific lesion of basal forebrain cholinergic projections abolished the visually-induced neuronal activity of the layer IV of the primary visual cortex. The present study investigated further which cell types immunoreactive for c-Fos were modulated by the cholinergic afferents. Twenty male Long Evans Rats (275-300g) were anaesthetized with urethane (1.3g/kg). C-Fos immunocytochemistry was used as a single cell resolution marker of functional activity induced by sinusoidal grating in the visual cortex in control condition, specific lesion of the cholinergic fibers using 192-IgG saporin, muscarinic inhibition by scopolamine (1mg/kg) or NMDA receptors inhibition by CPP (10mg/kg). c-Fos/Parvalbumin and c-Fos/rat-brain-pyramidal-cells-marker double immunocytochemistry was performed to determine the localization of the visually-induced c-Fos immunoreactivity within the GABAergic interneurons or pyramidal cells of the layer IV of the rat cortex. The results demonstrated that the c-Fos immunoreactivity evoked by patterned stimulation in layer IV was rarely (less than 5%) co-localized with either parvalbumin or rat-brain-pyramidal-cells-marker. In addition, this functional activity was blocked by a cholinergic deficit but was independent of NMDA receptors transmission, since their inhibition by CPP did not affect the activity-dependent c-Fos immunoreactivity. These results suggest an effect of the patterned visual stimulation and the cholinergic fibers on the excitatory spiny stellate cells rather than the GABAergic or pyramidal cells. It suggests a role of the basal forebrain cholinergic neurons in the modulation of the thalamo-cortical transmission rather than local cortical microcircuitry in the rat visual cortex.

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

Miller JP, McAuley JD, Pang KC (2006) Effects of selective cholinergic NBM lesions on short-interval timing. Neuroscience 2006 Abstracts 572.24. Society for Neuroscience, Atlanta, GA.

Summary: The nucleus basalis magnocellularis (NBM) and its connection to the frontal cortex are important for timing short durations and divided attention. Although the NBM provides the major cholinergic input to the frontal cortex, GABAergic and other neurons are also located in the NBM and project to neocortex. To examine the role of the NBM in timing and attention, previous investigators used non-selective lesions of the NBM using ibotenic acid (IBO). In the present study, we examined the importance of cholinergic NBM neurons in timing using the selective immunotoxin 192-IgG saporin (SAP). Fisher 344 rats were trained on a peak-interval (PI) procedure using fixed-intervals of 12 s and 24 s. Once trained, stereotaxic surgeries where conducted on the rats and either SAP or nothing (SHAM) was administered into the NBM to create selective cholinergic or control lesions respectively. Preliminary results show that SAP did not alter peak times (SHAM: 11.82 s & 22.59 s versus SAP: 11.98 s & 22.88 s) or coefficient of variability (CV, SHAM: 0.41 & 0.45 versus SAP: 0.44 & 0.47). However, upon inspection of the brains, SAP lesions did not reduce the number of cholinergic neurons in the NBM. In a separate study using the PI procedure with a single fixed-interval of 18 s, IBO altered timing accuracy as measured by the absolute difference in peak times (pre-op versus post-op: SHAM = 0.60 s; IBO = 1.94 s) and altered variability as measured by the change in CV (pre-op versus post-op: SHAM = 0.02; IBO = 0.20). Preliminary results with IBO showing a non-directional reduction in accuracy are different from previous studies that have reported systematic overestimation of duration, although in our study the damage caused by IBO was restricted to the anterior NBM. Current studies are further evaluating the role of NBM neurons in timing with more selective and complete cholinergic lesions using SAP and more complete non-selective lesions using IBO.

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)