Foxp2 regulates gene networks implicated in neurite outgrowth in the developing brain.

Forkhead-box protein P2 is a transcription factor that has been associated with intriguing aspects of cognitive function in humans, non-human mammals, and song-learning birds. Heterozygous mutations of the human FOXP2 gene cause a monogenic speech and language disorder. Reduced functional dosage of the mouse version (Foxp2) causes deficient cortico-striatal synaptic plasticity and impairs motor-skill learning. Moreover, the songbird orthologue appears critically important for vocal learning. Across diverse vertebrate species, this well-conserved transcription factor is highly expressed in the developing and adult central nervous system. Very little is known about the mechanisms regulated by Foxp2 during brain development. We used an integrated functional genomics strategy to robustly define Foxp2-dependent pathways, both direct and indirect targets, in the embryonic brain. Specifically, we performed genome-wide in vivo ChIP-chip screens for Foxp2-binding and thereby identified a set of 264 high-confidence neural targets under strict, empirically derived significance thresholds. The findings, coupled to expression profiling and in situ hybridization of brain tissue from wild-type and mutant mouse embryos, strongly highlighted gene networks linked to neurite development. We followed up our genomics data with functional experiments, showing that Foxp2 impacts on neurite outgrowth in primary neurons and in neuronal cell models. Our data indicate that Foxp2 modulates neuronal network formation, by directly and indirectly regulating mRNAs involved in the development and plasticity of neuronal connections.

Galanin: a potential role in mesolimbic dopamine-mediated instrumental behavior.

The involvement of the neuropeptide galanin in the consumption of the primary "commodities" of food and water is well established. However, the present review describes anatomical and behavioral evidence that suggests that galanin may also modulate ascending mesolimbic dopamine function and thereby play an inhibitory role in the systems by which instrumental behavior is energized toward acquiring primary commodities. General anatomical frameworks for this interaction are presented and future studies that could evaluate it are discussed.

Galanin stimulation of feeding is blocked by the addition of a response requirement.

Administration of the neuropeptide galanin increases food intake in laboratory rats and mice, however this increase has only been observed under conditions of free-feeding. As there is a growing distinction between consummatory and instrumental behavior, we assessed whether galanin would differentially affect food consumption when food was freely available or when the same food was response-contingent. We also tested whether food restriction would interact with galanin's effect on food consumption in either condition. As in previous studies, galanin significantly increased food consumption under free access conditions. However, when food was contingent upon lever-pressing, galanin had no such stimulatory effect. Food-restriction increased basal feeding levels in both tasks but there was no interaction between food restriction and free or response-contingent food intake. These results demonstrate that galanin-induced feeding stimulation is limited to conditions of free access and support the theoretical distinction between consummatory and instrumental behavior.

Intracerebroventricular administration of galanin decreases free water intake and operant water reinforcer efficacy in water-restricted rats.

The 29/30 amino acid neuropeptide galanin coexists with vasopressin in the hypothalamus and has been shown to inhibit the actions of vasopressin and aldosterone, suggesting an inhibitory role for galanin in physiological water retention mechanisms and water seeking and water consumption behavior. Little work, however, has examined a role for galanin in water intake regulation. Furthermore, many experiments that have reported galanin-induced impairments in the performance of tasks thought to measure learning and memory have used water restriction routines and water reinforcers to maintain responding. Therefore, the present study examined the effects of intracerebroventricularly administered galanin (5.0-20.0 microg/5 microl) on free water consumption during a 10 min test session and a follow up open field exploration, an operant progressive ratio (PR) schedule, a test used to assess reinforcer strength, and an operant fixed time schedule (FT 20) in 23.5h water restricted rats. Finally, in an additional experiment that was designed to simulate the effects of a galanin-induced decrease in water reinforcer efficacy, the rats were allowed access to water prior to testing in an operant delayed non-matching to position (DNMTP) task. A galanin-induced decrease in water consumption was observed in both the free access test and the FT 20 at the 20 microg dose, but no significant galanin-induced alterations in open field behavior. A decrease in responses emitted and rewards received was observed on the PR schedule at the 5, 10, and 20 microg doses. Pre-session access to water significantly reduced the number of trials per session in the DNMTP but did not reduce accuracy. This study is the first to observe a galanin-induced reduction in water intake and reinforced operant behavior, and suggests that galanin may play a role in regulating water intake and reinforcement. However, the present data also suggest that DNMTP choice accuracy deficits observed previously cannot be attributed to a galanin-induced change in reinforcer efficacy.

Assessment of new functional roles for galanin in the CNS.

There is considerable evidence that galanin plays an important role in food intake, nociception, stress reactivity, sexual behavior, and learning. However, its involvement in other important behavioral processes, especially higher cognition, has not been systematically investigated. This review summarizes our recent efforts to explore the role of galanin in executive processes as well as in fundamental motivational and motor productive processes that are essential to the behavioral assessment of cognitive constructs in rodents. Our work points to a role in reward processes and physiological water balance regulation, and argues against a role for galanin in fine motor production and maintenance, simple visual discrimination, and perseveration.

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.

Galanin and perseveration.

Galanin is a 29/30 amino acid neuropeptide that has been shown to impair learning and memory task performance and also have roles in somatosensation, stress responses, sexual behavior, and feeding regulation. However, little is known about galanin involvement in higher cognitive processes, especially executive processes. Perseveration is a classic sign of frontal cortex damage and failure of executive control. Galanin has been shown to disrupt the performance of maze delayed alternation tasks and the operant, spatial delayed nonmatch-to-position (DNMTP) working memory task, tests especially sensitive to perseverative responding. To better understand this potential involvement of galanin in executive control, the present study tested the hypothesis that galanin induces perseveration. The first experiment examined the effects of galanin (10, 20 microg i.c.v.) on the performance of a simple operant response alternation task in which stimuli were assigned to one of two spatially distinct locations to produce extended sequences of presentations to one location, separated by a 10-s intertrial interval. The second experiment looked at the effects of galanin (5, 20 microg i.c.v.) on the performance of non-delayed match-to-position and nonmatch-to-position conditional discrimination operant tasks in which a minimal 1.0 s time interval separated responses. Finally, the effects of galanin (10, 20 microg i.c.v.) on delayed match-to-position (DMTP) performance were examined to determine whether response alternation (i.e., nonmatching) was critical to observing a galanin-induced impairment in this task. Galanin reduced the rate of trial completion in all the tasks, but did not alter simple or conditional discrimination accuracy. Galanin (10 microg) impaired DMTP performance in a delay-independent manner. Together, these data suggest that galanin does not produce perseveration, but are consistent with a galanin-induced decrease in reinforcer strength.

Regulation of feeding by galnon.

Galanin is a neuropeptide that has been implicated in multiple bioactivities, inter alia eating disorders. In this study, we have examined the effects of galnon, a novel low molecular weight galanin receptor ligand. Previous studies have shown that galnon acts as a systemically active, blood-brain barrier crossing agonist on galanin signaling both in vitro and in vivo, inhibiting pentylenetetrazole-induced seizures. Here, intracerebroventricular (10-20 microg) and intraperitoneal (1.5-5 mg/kg) administration of galnon induced a strong, dose-dependent reduction of food intake in rats and mice. This reduction in feeding occurred without reducing general activity and was shown to be attenuated by an intracerebroventricular administration of M35, a peptide galanin antagonist. These data demonstrate that galnon is a promising tool for studies of the involvement of galanin in feeding disorders and other behavioral processes.

Intracerebroventricularly administered galanin does not alter operant reaction time or differentially reinforced high rate schedule operant responding in rats.

Galanin (Gal) is a 29/30 amino acid neuroendocrine peptide that impairs learning and memory processes, stimulates feeding, and modulates somatosensory, sex, and stress responses. Anatomical markers for Gal are found throughout the brain, including in the caudate-putamen and substantia nigra motor regions. Many of the behavioral tests that have been used to study the involvement of Gal in complex behavioral processes are motorically demanding, but no research has specifically investigated the involvement of Gal in response initiation or the maintenance of fine motor action. Therefore, the present study examined the effects of intraventricularly administered Gal on two highly sensitive operant tasks designed to detect alteration of these response properties. Response initiation was studied using a light-dark discrimination reaction time task that required a correct response within 2.5s of a spatially and temporally uncertain stimulus onset. The ability to perform high local rates of responding was studied using an operant differential reinforcement of high rate (DRH) of responding task. Gal (10-20 microg, i.c.v.) did not alter reaction time or inter-response time distributions in either task, though did substantially reduce the total number of responses and reinforcers obtained on the DRH schedule. These results are consistent with a Gal-induced reduction of reinforcer efficacy rather than Gal-disruption of response initiation or response patterning.