Joshua A. Burk

DIFFERENTIAL CORTICAL ACETYLCHOLINE RELEASE IN RATS PERFORMING A SUSTAINED ATTENTION TASK VERSUS BEHAVIORAL CONTROL TASKS THAT DO NOT EXPLICITLY TAX ATTENTION

The present study used microdialysis techniques to compare acetylcholine release in the frontoparietal cortex of rats performing in a task requiring sustained attention with that of rats performing in two control procedures. The two control procedures were a fixed-interval 9-s schedule of reinforcement assessing primarily the effects of operant responding and comparable reward rates, and an operant procedure designed to test the effects of lever extension to prompt responding. These two control procedures involved comparable sensory-motor and motivational variables to those of the sustained attention task, but did not explicitly tax attentional processes. Performance of the sustained attention task was associated with a significant increase in cortical acetylcholine efflux, reaching a maximum of nearly 140%. Performance of the two control procedures was associated with significantly smaller (approximately 50%) increases in cortical acetylcholine release. This robust dissociation between attentional and control performance-associated increases in cortical acetylcholine release resulted, in part, from the elimination of the pre-task transfer of the animals into the operant chambers and the associated increases in acetylcholine release observed in previous studies. The present results support the hypothesis that demands on attentional performance, as opposed to the frequency of lever pressing, reward delivery and other task-related variables, selectively activate the basal forebrain corticopetal cholinergic system.

Orexin/hypocretin modulation of the basal forebrain cholinergic system: Role in attention

The basal forebrain cholinergic system (BFCS) plays a role in several aspects of attentional function. Activation of this system by different afferent inputs is likely to influence how attentional resources are allocated. While it has been recognized for some time that the hypothalamus is a significant source of projections to the basal forebrain, the phenotype(s) of these inputs and the conditions under which their regulation of the BFCS becomes functionally relevant are still unclear. The cell bodies of neurons expressing orexin/hypocretin neuropeptides are restricted to the lateral hypothalamus and contiguous perifornical area but have widespread projections, including to the basal forebrain. Orexin fibers and both orexin receptor subtypes are distributed in cholinergic parts of the basal forebrain, where application of orexin peptides increases cell activity and cortical acetylcholine release. Furthermore, disruption of orexin signaling in the basal forebrain impairs the cholinergic response to an appetitive stimulus. In this review, we propose that orexin inputs to the BFCS form an anatomical substrate for links between arousal and attention, and that these interactions might be particularly important as a means by which interoceptive cues bias allocation of attentional resources toward related exteroceptive stimuli. Dysfunction in orexin-acetylcholine interactions may play a role in the arousal and attentional deficits that accompany neurodegenerative conditions as diverse as drug addiction and age-related cognitive decline.

Interactions between aging and cortical cholinergic deafferentation on attention

Pre-existing trauma to basal forebrain corticopetal cholinergic neurons has been hypothesized to render this system vulnerable to age-related processes. The present longitudinal study assessed the interactions between the effects of partial cortical cholinergic deafferentation and aging on sustained attention performance. After pre-surgical training, animals were given sham-surgery or bilateral infusions of the immunotoxin 192 IgG-saporin into the basal forebrain. The lesion was intended to yield a limited loss of cortical cholinergic inputs and thus to produce minor immediate effects on sustained attention performance. All animals were tested continuously until age 36 months. The attentional performance of lesioned and sham-lesioned animals did not dissociate until age 31 months, when the lesioned animals exhibited an impairment in overall sustained attention performance. Importantly, this impairment interacted with the effects of time-on-task, and thus reflected a specific impairment in attentional processes. These results support the notion that pre-existing damage to the basal forebrain corticopetal cholinergic neurons yields age-related impairments in the attentional capabilities that depend on the integrity of this neuronal system.

Introduction of a retention interval in a sustained attention task in rats: effects of a visual distracter and increasing the inter-trial interval.

The impact of manipulating explicit attentional demands on working memory has not been well studied in rodents. The present experiment was designed to test the effects of incorporating a retention interval in a two-lever sustained attention task that requires discrimination of visual signals and non-signals and that has previously been shown to yield valid measures of attention in the rat. Upon establishing baseline performance, additional manipulations, including presentation of a visual distracter and increasing the length and variability of the inter-trial interval were conducted. During baseline conditions, accurate detection of signals, but not non-signals, decreased as the retention interval was increased. Presentation of a flashing houselight throughout the session eliminated delay-dependent detection of signals. Increasing the inter-trial interval improved detection of signals and decreased detection of non-signals at the longest retention interval. Finally, increasing the variability of the inter-trial interval did not have significant effects on performance above and beyond the effects of increasing the inter-trial interval. The present experiment demonstrates that manipulation of explicit attentional demands can alter working memory performance in the rat. This task may be employed to understand the neuropharmacological and neuroanatomical substrates mediating memory while attentional load is systematically varied.

Adolescent nicotine exposure disrupts context conditioning in adulthood in rats.

Despite the prevalence of smoking among adolescents, few studies have assessed the effects of adolescent nicotine exposure on learning in adulthood. In particular, it remains unclear whether adolescent nicotine exposure has effects on hippocampus-dependent learning that persist into adulthood. The present experiment examined whether there were effects of adolescent nicotine exposure on context conditioning, a form of learning dependent on the integrity of the hippocampus, when tested during adulthood. Rats were exposed to nicotine during adolescence (postnatal days [PD] 28-42) via osmotic minipump (0, 3.0 or 6.0mg/kg/day). Context conditioning occurred in early adulthood (PD 65-70). Animals were exposed to an experimental context and were given 10 unsignaled footshocks or no shock. Additional groups were included to test the effects of adolescent nicotine on delay conditioning, a form of learning that is not dependent upon the hippocampus. Conditioning was assessed using a lick suppression paradigm. For animals in the context conditioning groups, adolescent nicotine resulted in significantly less suppression of drinking in the presence of context cues compared with vehicle-pretreated animals. For animals in the delay conditioning groups, there was a trend for adolescent nicotine (3.0mg/kg/day) to suppress drinking compared to vehicle-pretreated animals. There were no differences in extinction of contextual fear or cued fear between rats previously exposed to vehicle or nicotine. The data indicate that adolescent nicotine administration impairs context conditioning when animals are trained and tested as adults. The present data suggest that adolescent nicotine exposure may disrupt hippocampus-dependent learning when animals are tested during adulthood.

Effects of excitotoxic thalamic intralaminar nuclei lesions on attention and working memory

In rats, lesions of the thalamic intralaminar nuclei (ILn) impair measures of working memory, but it is unclear whether alterations of attention contribute to the mnemonic deficits. The present experiment tested the effects of ILn lesions on a two-lever attention task that required discrimination of visual signals and non-signals. Rats were trained presurgically in the task and then received sham surgery or infusions of n-methyl-d-aspartate (NMDA) into the ILn to induce excitotoxic lesions. ILn lesions transiently decreased accurate detection of signals. ILn lesions also increased omissions. Compared to sham-lesioned rats, ILn-lesioned animals were not differentially affected when task demands were increased by presenting a visual distracter. Finally, a retention interval was incorporated into the task to assess whether the lesions affected acquisition of a working memory version of this behavioral paradigm. Unlike sham-lesioned animals, ILn-lesioned rats did not demonstrate a significant improvement in signal detection when a retention interval was introduced. The transient lesion-induced deficits in the attention task suggest that, in rats, the ILn may contribute to aspects of attentional processing, but through neural re-organization or activity in other regions, there is compensation for the loss of ILn functioning. The ILn appear to be necessary for maintaining performance when working memory demands are increased.

Construct validity of an operant signal detection task for rats

Many psychoactive drugs produce simultaneous effects on a variety of psychological processes. Behavioral measures in tasks designed to assess cognitive processes in rodents should be able to characterize and dissociate these multiple influences. The present study evaluated how error measures in a classic two-choice operant spatial signal detection paradigm were affected by procedural manipulations of the motivational state of the rat, stimulus properties, and alterations of the inter-trial interval. The experiments were conducted in a two lever operant chamber in which a cue lamp was mounted over each lever. The rats were trained to respond quickly to a short illumination of one of the cue lamps at one of three durations (100, 300 or 1000 ms), presented in a random order. The procedural manipulations were (1) to allow pre-session water access to the normally water-restricted subjects, (2) to vary the intertrial interval (ITI) between sessions, (3) to reduce the intensity of the discriminative stimuli, and (4) to manipulate the variability of the ITI within a session. Stimulus duration-dependent decreases of detection accuracy were observed following pre-session water access and when the intertrial interval was decreased. A reduction of stimulus intensity resulted in decreased accuracy at all stimulus durations. Varying the ITI within the session produced stimulus duration-independent alterations of detection accuracy but no change in the frequency of errors of omission. These findings show that distinct patterns of performance deficits result from manipulating different components of this task and that errors of omission and commission often co-vary and raise questions about the definitions of vigilance and sustained attention as these constructs apply to signal detection tasks that present spatially distinct stimuli.

Adolescent transitions in reflexive and non-reflexive behavior: Review of fear conditioning and impulse control in rodent models

Adolescence is a time of critical brain changes that pave the way for adult learning processes. However, the extent to which learning in adolescence is best characterized as a transitional linear progression from childhood to adulthood, or represents a period that differs from earlier and later developmental stages, remains unclear. Here we examine behavioral literature on associative fear conditioning and complex choice behavior with rodent models. Many aspects of fear conditioning are intact by adolescence and do not differ from adult patterns. Sufficient evidence, however, suggests that adolescent learning cannot be characterized simply as an immature precursor to adulthood. Across different paradigms assessing choice behavior, literature suggests that adolescent animals typically display more impulsive patterns of responding compared to adults. The extent to which the development of basic conditioning processes serves as a scaffold for later adult decision making is an additional research area that is important for theory, but also has widespread applications for numerous psychological conditions.

Effects of gonadectomy and androgen supplementation on attention in male rats

Androgens are hypothesized to enhance aspects of mnemonic processing. However, it is unclear whether the memory improvement is associated with changes in earlier aspects of information processing, such as attention. The present experiments examined the effects of gonadectomy or supplementation with testosterone or dihydrotestosterone on performance of male rats in a two-lever attention task that required discrimination of visual signals and non-signals. In Experiment 1, Long-Evans rats were trained in the attention task and then underwent gonadectomy or sham-surgery. Postsurgically, animals were tested for 20 sessions in the attention task and then received manipulations designed to increase attentional demands. Gonadectomized and sham-treated animals performed similarly during immediate postsurgical testing and across all manipulations. Finally, the effects of administering the muscarinic receptor antagonist scopolamine (0, 0.1, and 0.2 mg/kg) on attentional performance were assessed for all animals. Scopolamine decreased accuracy of signal detection but did not differentially affect gonadectomized and sham-treated animals. In Experiment 2, a new group of rats (not gonadectomized) was trained to perform the attention task and subsequently administered testosterone (0, 0.1, and 0.5 mg/kg) or dihydrotestosterone (0, 0.1, and 0.5mg/kg) prior to performing the standard version of the attention task and in the presence of a visual distractor. Testosterone (0.5 mg/kg) decreased accuracy on non-signal trials and, at 0.1 mg/kg, decreased latencies to retrieve a reward. Dihydrotestosterone (0.5 mg/kg) decreased accuracy on non-signal trials during visual distractor sessions. The present data do not support the hypothesis that alterations in attention critically mediate androgen-induced changes in mnemonic processing. Supra-physiological androgen levels appear to be capable of impairing attentional processing.

Orexin A-induced enhancement of attentional processing in rats: role of basal forebrain neurons

RationaleOrexins are neuropeptides released in multiple brain regions from neurons that originate within the lateral hypothalamus and contiguous perfornical area. The basal forebrain, a structure implicated in attentional processing, receives orexinergic inputs. Our previous work demonstrated that administration of an orexin-1 receptor antagonist, SB-334867, systemically or via infusion directly into the basal forebrain, can disrupt performance in a task that places explicit demands on attentional processing.ObjectivesGiven that the orexin-1 receptor binds orexin A with high affinity, we tested whether orexin A could enhance attention in rats.MethodsAttentional performance was assessed using a task that required discrimination of variable duration visual signals from trials when no signal was presented. We also tested whether infusions of orexin A into the lateral ventricle could attenuate deficits following lesions of medial prefrontal cortical cholinergic projections that arise from the basal forebrain.ResultsInfusions of orexin A into the basal forebrain attenuated distracter-induced decreases in attentional performance. Orexin A attenuated deficits in lesioned animals when a visual distracter was presented.ConclusionThe present results support the view that orexin A can enhance attentional performance via actions in the basal forebrain and may be beneficial for some conditions characterized by attentional dysfunction due to disruption of cortical cholinergic inputs.