Basal Forebrain Sites Research Articles

Reward cues readily direct monkeys\u2019 auditory performance resulting in broad auditory cortex modulation and interaction with sites along cholinergic and dopaminergic pathways

In natural settings, the prospect of reward often influences the focus of our attention, but how cognitive and motivational systems influence sensory cortex is not well understood. Also, challenges in training nonhuman animals on cognitive tasks complicate cross-species comparisons and interpreting results on the neurobiological bases of cognition. Incentivized attention tasks could expedite training and evaluate the impact of attention on sensory cortex. Here we develop an Incentivized Attention Paradigm (IAP) and use it to show that macaque monkeys readily learn to use auditory or visual reward cues, drastically influencing their performance within a simple auditory task. Next, this paradigm was used with functional neuroimaging to measure activation modulation in the monkey auditory cortex. The results show modulation of extensive auditory cortical regions throughout primary and non-primary regions, which although a hallmark of attentional modulation in human auditory cortex, has not been studied or observed as broadly in prior data from nonhuman animals. Psycho-physiological interactions were identified between the observed auditory cortex effects and regions including basal forebrain sites along acetylcholinergic and dopaminergic pathways. The findings reveal the impact and regional interactions in the primate brain during an incentivized attention engaging auditory task.

Neural responses to aggressive challenge correlate with behavior in nonbreeding sparrows

The present study was conducted on captive male song sparrows (Melospiza melodia) during the nonbreeding season in order to (1) examine Fos and Zenk responses of basal forebrain sites to simulated territorial intrusion and (2) determine how those responses relate to aggression. Numerous forebrain areas showed significant Fos and Zenk responses to simulated territorial intrusion, and in several areas of the hypothalamus and lateral septum, these responses were negatively correlated with aggressive behavior. Homologous areas in mammals show greater responses in subordinate subjects than in dominant subjects. Thus, these brain areas may be responsive to social stressors across a wide range of vertebrates.

The Nitric Oxide Synthase InhibitorNG-Nitro-l-Arginine Increases Basal Forebrain Acetylcholine Release during Sleep and Wakefulness

Cholinergic neurotransmission in the basal forebrain changes across the sleep/wake cycle, and considerable data show cortical activation by ACh originating from basal forebrain neurons. These findings have stimulated efforts to elucidate molecular modulators of ACh release within the basal forebrain. Basal forebrain cholinergic neurons contain nitric oxide synthase (NOS), the enzyme that produces the gaseous neuromodulator nitric oxide. This study tested the hypothesis that administration of an NOS inhibitor to the basal forebrain would alter basal forebrain ACh release, sleep, and respiratory rate. Seven cats were instrumented for recording sleep and wakefulness and for <i>in vivo</i> microdialysis and microinjection. Compared with Ringer9s solution (control), microdialysis delivery of the NOS inhibitor<i>N</i>^G-nitro-l-arginine (NLA; 10 mm) increased ACh release during wakefulness (33%), non-rapid eye movement (NREM) sleep (70%), and rapid eye movement (REM) sleep (16%). Mean ± SEM ACh levels (pmol/10 min) during control and NLA dialysis, respectively, were 0.58 ± 0.03 and 0.77 ± 0.06 in wakefulness, 0.36 ± 0.01 and 0.61 ± 0.06 in NREM sleep, and 0.68 ± 0.06 and 0.79 ± 0.09 in REM sleep. Increases in ACh release were not evoked by dialysis delivery of the less active enantiomer<i>N</i>^G-nitro-d-arginine. Dialysis administration of NLA did not alter respiratory rate. Sleep-dependent changes in basal forebrain ACh release were localized specifically to lateral basal forebrain regions and did not occur in medial basal forebrain sites. Microinjection of NLA into the lateral basal forebrain did not significantly alter the sleep/wake cycle. In contrast to NLA-induced depression of REM sleep and ACh release in the cat pons, the present results demonstrate that NLA increased ACh release in the cat basal forebrain and had no effect on sleep. The different effects of NLA on ACh release in the cat pons and cat basal forebrain may prove relevant for developing compounds that differentially alter cholinergic neurotransmission in specific brain regions.

The nitric oxide synthase inhibitor NG-Nitro-L-arginine increases basal forebrain acetylcholine release during sleep and wakefulness.

Cholinergic neurotransmission in the basal forebrain changes across the sleep/wake cycle, and considerable data show cortical activation by ACh originating from basal forebrain neurons. These findings have stimulated efforts to elucidate molecular modulators of ACh release within the basal forebrain. Basal forebrain cholinergic neurons contain nitric oxide synthase (NOS), the enzyme that produces the gaseous neuromodulator nitric oxide. This study tested the hypothesis that administration of an NOS inhibitor to the basal forebrain would alter basal forebrain ACh release, sleep, and respiratory rate. Seven cats were instrumented for recording sleep and wakefulness and for in vivo microdialysis and microinjection. Compared with Ringer's solution (control), microdialysis delivery of the NOS inhibitor N(G)-nitro-l-arginine (NLA; 10 mm) increased ACh release during wakefulness (33%), non-rapid eye movement (NREM) sleep (70%), and rapid eye movement (REM) sleep (16%). Mean +/- SEM ACh levels (pmol/10 min) during control and NLA dialysis, respectively, were 0.58 +/- 0.03 and 0.77 +/- 0.06 in wakefulness, 0.36 +/- 0.01 and 0.61 +/- 0.06 in NREM sleep, and 0.68 +/- 0.06 and 0.79 +/- 0.09 in REM sleep. Increases in ACh release were not evoked by dialysis delivery of the less active enantiomer N(G)-nitro-d-arginine. Dialysis administration of NLA did not alter respiratory rate. Sleep-dependent changes in basal forebrain ACh release were localized specifically to lateral basal forebrain regions and did not occur in medial basal forebrain sites. Microinjection of NLA into the lateral basal forebrain did not significantly alter the sleep/wake cycle. In contrast to NLA-induced depression of REM sleep and ACh release in the cat pons, the present results demonstrate that NLA increased ACh release in the cat basal forebrain and had no effect on sleep. The different effects of NLA on ACh release in the cat pons and cat basal forebrain may prove relevant for developing compounds that differentially alter cholinergic neurotransmission in specific brain regions.

Amphetamine acts within the medial basal forebrain to initiate and maintain alert waking

Amphetamine-like stimulants exert well-known arousal-enhancing actions. Surprisingly, little is known concerning the neuroanatomical substrates through which these drugs enhance arousal. Previous work implicates a number of basal forebrain structures in the regulation of behavioral state. The current studies examined the effects of amphetamine infusions made directly within basal forebrain sites on behavioral, electroencephalographic, and electromyographic indices of arousal in anesthetized and unanesthetized rat. In the anesthetized rat, amphetamine elicited prolonged epochs of bilateral electroencephalographic activation when infused unilaterally (3.75 μg/150 nl) into an extended region of the medial basal forebrain, demarcated anteriorally by the anterior portion of the medial septal area (which includes posterior accumbens shell) and posteriorally by the posterior aspect of the preoptic area of the hypothalamus. In the unanesthetized (undisturbed, resting) rat, amphetamine infusions into this region elicited prolonged epochs of alert waking, which at the lowest dose (3.75 μg), qualitatively resembled normal waking. Infusions placed lateral (including within the substantia innominata), anterior (including within the core subregion of the nucleus accumbens), posterior, or dorsal to these structures, as well as directly within the lateral ventricles did not alter electroencephalographic or behavioral measures. These results indicate that a region of the medial basal forebrain, extending from the anterior medial septum/accumbens shell to the posterior preoptic area, is a site within which amphetamine-like stimulants act to enhance behavioral and electroencephalographic measures of arousal.

Differential control of cortical activity by the basal forebrain in rats: a role for both cholinergic and inhibitory influences

Using microdialysis and high-performance liquid chromatography, we measured acetylcholine (ACh) release simultaneously from two cortical sites in anesthetized rats. One site was always in the somatosensory cortex, and the other was in either the visual or the motor cortex. After baseline measurements were obtained, selected sites in the basal forebrain (BF) were stimulated to increase ACh release. Some BF sites provoked more release in one microdialysis probe than in the other, suggesting some degree of corticotropic organization of the cholinergic projections from the BF. BF sites optimal for release from the visual cortex were separated from optimal sites for release from the somatosensory cortex by greater distances than were the best sites for release from the somatosensory and the motor cortex. Stimulation of a single BF site often provoked similar release from the latter two cortical areas. Electrical stimulation of the BF also modified cortical neuronal activity. Activation of some BF sites provoked an intense discharge of many neurons in the vicinity of the cortical recording electrode, and the same stimulus site in the BF provoked release of large amounts of ACh in the cortex. Stimulation of other BF sites produced strong inhibition of ongoing cortical activity and no increase in cortical ACh release. When other sites were stimulated, they had no effect or they generated stereotyped bursting patterns in the cortex without any observable effect on ACh release. BF sites that generated inhibition of cortical neural activity were generally located near the sites that activated the cortex and provoked release of ACh. These data suggest an elaborate control of the sensory cortex by a mechanism involving both gamma-aminobutyric acid-containing and cholinergic neurons of the BF.

Effects of excitotoxic lesions of the basal forebrain on MFB self-stimulation

Electrolytic lesions of the anterior medial forebrain bundle (MFB) have been shown to attenuate the rewarding impact of stimulating more caudal MFB sites. In the present study, excitotocic lesion were employed to determine the relative contribution of somata or fibers of passage contributing to that effect. Changes in reward efficacy were infrared, at three currents, from lateral displacements of the curve relating the rate of responding to the number of stimulation pulses per train. After baseline data were collected from stimulation sites in the lateral hypothalamus (LH) and the ventral tegmental area (VTA), 70 nmol of N-methyl- d-aspartic acid was injected via cannulae aimed at basal forebrain sites. Three subjects were injected with vehicle and served as controls. In 5 out of 15 cases, lesions encompassing the lateral preoptic area, anterior LH, and substantia innominata resulted in long-lasting, large increases (0.2–0.47 log 10 units) in the number of pulses required to maintain half-maximal rates of self-stimulation for low currents delivered via the LH electrode; smaller increases (0.08–0.33 log 10 units) were noted at moderate and high currents. Seven rats with similar or more dorsally located damage showed moderate or transient increases in the number of pulses required to maintain half-maximal rates of LH or VTA self-stimulation. Vehicle injections did not affect behaviour. Varying degrees of demyelinaion were seen, mostly removed from the electrode tip, and in locations that varied substantially across subjects manifesting similar changes in self-stimulation. These results support the notion that somata in the basal forebrain give rise to some of the directly activated fibers subserving self-stimulation of the MFB.

Magnocellular nuclei of the basal forebrain: substrates of sleep and arousal regulation.

Magnocellular regions of the basal forebrain (BF) are recognized as important sites of sleep-wake regulation. Evidence is reviewed for the coexistence within the BF of mechanisms that regulate neocortical and limbic system arousal along with mechanisms that promote sleep. Arousal-related functions are mediated by a system of magnocellular cholinergic neurons. BF cholinergic neurons project monosynaptically to the entire neocortex and limbic telencephalon, exert excitatory effects on target cells and participate in the regulation of activated EEG patterns characteristic of waking and REM sleep. Evidence suggests that, within the waking state, the BF cholinergic system modulates processing of sensory information in the neocortex and is involved in cognitive processes. One or more noncholinergic cell types are responsible for the sleep-promoting functions of the BF. Neurons that display elevated discharge rates during transitions from waking to sleep and during nonREM sleep have been recorded in BF sites were electrical stimulation evokes sleep and experimental lesions cause insomnia. BF neurons function to promote sleep, in part, via descending inhibition of caudal hypothalamic and brainstem activating systems. GABAergic neurons located within magnocellular regions of the BF are hypothesized to mediate sleep-promoting actions. Afferents to the BF from hypothalamic and brainstem regions are functionally important for sleep-wake regulation. Thermosensitive inputs from the anterior hypothalamus modulate the activity of BF sleep- and arousal-related cell types. Excitatory effects of brainstem inputs to BF arousal-related cells have been documented. Additional evidence supports a critical role for GABAergic-cholinergic interactions, both within the magnocellular BF and at cortical and diencephalic sites, in the regulation of behavioral state.

Poststimulation excitability of ventral pallidum self-stimulation neurons.

The degree of neural recovery from refractoriness was inferred in rats self-stimulating with pairs of pulses in the ventral pallidum. The prerecovery intrapair interval varied from 0.5 to 1.0 ms, depending on brain site. At some sites, recovery reached its maximum within less than 1.6 ms whereas, at the majority of sites, a substantial amount of recovery occurred at delays longer than 1.2 ms. The shortest recovery estimates were not fundamentally different from those obtained from sites lying along the medial forebrain bundle. The longest recovery estimates were similar to those obtained from cortical and basal forebrain sites. The differences in recovery noted between sites and the presence of step-like patterns in the recovery curves suggest the presence of neural heterogeneity within the ventral pallidal substrates of reward.

Localisation of mRNA encoding the protein precursor of galanin in the monkey hypothalamus and basal forebrain.

The hypothalamic and basal forebrain sites of synthesis of preprogalanin mRNA were identified in three adult monkeys (Macaca fascicularis) by in situ hybridisation performed with a radiolabelled cRNA probe transcribed from human preprogalanin cDNA. With stringent hybridisation conditions, the cRNA probe was hybridised to free-floating sections containing structures contiguous with the rostral hypothalamus through to the caudal limit of the hypothalamus as defined by the mammillary bodies. Specific hybridisation of the preprogalanin cRNA probe occurred throughout the hypothalamus but was particularly intense in the arcuate, paraventricular (parvicellular and magnocellular portions), and dorsomedial nuclei. Moderate hybridisation was found in the periventricular nucleus and scattered hybridisation in the medial preoptic nucleus. The medial preoptic area and the anterior and lateral hypothalamic areas showed moderate to intense hybridisation in scattered cells. A few cells in the tuberal portion and dorsal cap of the anterior portion of the supraoptic nucleus were labelled. Isolated cells were also labelled in the zona incerta. There was little labelling in the dorsal hypothalamic area but moderate labelling in the posterior hypothalamic area. Structures contiguous with the rostral hypothalamus including the diagonal band of Broca, bed nucleus of stria terminalis, substantia innominata, and basal nucleus of Meynert showed intense hybridisation. These data indicate a widespread distribution of preprogalanin mRNA in the monkey hypothalamus. A comparison with the previously reported distribution of preprogalanin mRNA in the rat, as well as with the distribution of galanin-like immunoreactivity in the rat and human, suggests some important species differences. Of particular interest were differences in the supraoptic, suprachiasmatic, and dorsomedial nuclei. The intense hybridisation throughout the paraventricular nucleus and in the rostral arcuate nucleus suggests that galanin may play a role in the regulation of both posterior and anterior pituitary function.

Spatial memory deficits in aged rats: contributions of monoaminergic systems

Age-dependent changes in monoaminergic systems and their relationship to senescent memory decline were investigated in 4- and 25–26-month-old, female, Fischer 344 rats. Spatial memory performance was tested on an 8-arm radial maze, and levels of norepinephrine (NE), dopamine (DA) and metabolites 3,4-dihydroxyphenylacetic acid and homovanillic acid, serotonin (5-HT) and metabolite 5-hydroxyindoleacetic acid were measured in brain areas which contribute to memory function — basal forebrain cholinergic nuclei, subfields of the hippocampus, frontal and entorhinal cortex — and in monoaminergic cell body areas. The performance of aged subjects was significantly impaired as compared to young subjects, and alterations of 20–60% in monoamine and metabolite levels were measured in specific brain areas of aged rats. Decreased NE levels were found in basal forebrain nuclei and cortical areas but not hippocampal subfields of aged rats. Changes in the 5-HT system were present in hippocampal, cortical and basal forebrain sites. Changes in the DA system were the most pervasive with aged rats showing decreased DA and/or metabolites in several basal forebrain nuclei, cortical areas, and the hippocampus. Aged rats showed 50% decreases of monoamines in locus coeruleus and substantia nigra and 30% decreases in the dorsal raphe nucleus. Some but not all of the changes correlated with memory performance. The present results in rats support evidence that age-dependent changes in monoaminergic function in discrete brain sites contribute to senescent memory decline and suggest that monoaminergic-cholinergic interactions within basal forebrain nuclei may be important in this decline.

Effects of basal forebrain stimulation on the waking discharge of neurons in the midbrain reticular formation of cats

Neurons in the lateral basal forebrain which discharge selectively during slow-wave sleep have been identified as projecting to the midbrain reticular formation. Such cells have been hypothesized to participate in sleep-related changes in reticular formation excitability. The effects of stimulation at these sites on reticular formation single unit discharge in behaving cats was quantified in the present study. Effects were compared to those evoked from medial forebrain sites, including the preoptic area/anterior hypothalamus. Stimulation at all of these basal forebrain sites typically produced biphasic responses, consisting of a brief, short-latency excitation, followed by discharge suppression. Stimulation at lateral sites resulted in significantly longer periods of discharge suppression compared to stimulation at medial sites. These results support the hypothesis that laterally situated basal forebrain neurons participate in the regulation of behavioral state, in part, via descending modulation of midbrain reticular formation arousal mechanisms.

Long-term enhancement of evoked potentials in cat somatosensory cortex produced by co-activation of the basal forebrain and cutaneous receptors.

Averaged evoked potentials from primary somatosensory cortex (SEPs) were recorded before and after pairing the peripheral stimuli with electrical activation of the basal forebrain (BF) in anesthetized cats. Four pulses at 400 Hz were delivered to the BF 120 ms before each cutaneous stimulus and 10 to 660 such pairings were found to produce an enlargement of the SEP in 10 of 11 animals. The average increase in amplitude of the initial peak of the SEP was 69%. The SEP remained enhanced in five of six animals that were tested an hour or more after the pairing, and in one case the SEP was tested 4.5 h after pairing without diminution. The effective BF sites were located in the substantia innominata and at the rostral pole of the globus pallidus, regions known to contain many cholinergic cell bodies. Enhancement occurred consistently only if stimulation of the BF site elicited a positive wave in the cortex at a latency of 11 to 18 ms. Repeated BF stimulation without cutaneous input did not produce a change in subsequent SEPs. The long-term changes described here may be involved in experimentally- and naturally-induced cortical reorganization.

Neurotransmitters in the cerebral cortex.

This article surveys the conventional neurotransmitters and modulatory neuropeptides that are found in the cerebral cortex and attempts to place them into the perspective of both intracortical circuitry and cortical disease. The distribution of these substances is related, where possible, to particular types of cortical neuron or to afferent or efferent fibers. Their physiological actions, where known, on cortical neurons are surveyed, and their potential roles in disease states such as the dementias, epilepsy, and stroke are assessed. Conventional transmitters that occur in afferent fibers to the cortex from brain-stem and basal forebrain sites are: serotonin, noradrenaline, dopamine, and acetylcholine. All of these except dopamine are distributed to all cortical areas: dopamine is distributed to frontal and cingulate areas only. The transmitter in thalamic afferent systems is unknown. Gamma aminobutyric acid (GABA) is the transmitter used by the majority of cortical interneurons and has a profound effect upon the shaping of receptive field properties. The vast majority of the known cortical peptides are found in GABAergic neurons, and the possibility exists that they may act as trophic substances for other neurons. Levels of certain neuropeptides decline in cases of dementia of cortical origin. Acetylcholine is the only other known transmitter of cortical neurons. It, too, is contained in neurons that also contain a neuropeptide. The transmitter(s) used by excitatory cortical interneurons and by the efferent pyramidal cells is unknown, but it may be glutamate or aspartate. It is possible that excitotoxins released in anoxic disease of the cortex may produce damage by acting on receptors for these or related transmitter agents.

Spinal neuronal inhibition and EEG synchrony by electrical stimulation in subcortical forebrain regions of the cat.

In cats anaesthetized with sodium pentobarbital and 70% N2O, single lumbar dorsal horn neurons were excited by controlled noxious radiant heating of glabrous hindpaw skin. The EEG was recorded from the pericruciate cortex and posterior lateral gyrus. Subcortical forebrain sites where electrical stimulation inhibited dorsal horn neuronal heat-evoked responses contralaterally were identified by mapping the caudate nucleus, internal capsule, septum, nucleus accumbens and basal forebrain regions. Inhibitory sites were mainly located in the ventral forebrain (ventral septum, diagonal band, basal forebrain). The caudate nucleus and internal capsule had a low incidence and effectiveness of inhibitory sites. In the basal forebrain, the incidence and effectiveness of inhibitory sites decreased from caudal to rostral regions. There was a rostral limit of inhibitory sites, both medially and laterally. The magnitude of inhibition increased with graded increases in brain stimulation intensity. The mean incremental increase in inhibition was greater for caudal than for rostral basal forebrain sites. Mean stimulus currents for threshold of inhibition and for inhibition to 50% of control heat responses were lower for caudal than for rostral sites. Responses of the dorsal horn neurons to increasing temperatures of noxious skin heating were monotonic linear functions over the temperature range studied (48-53 degrees C). Stimulation in both rostral and caudal basal forebrain decreased the slope of this stimulus-response function, with a greater decrease for caudal sites. Cortical EEG synchronization was evoked by stimulation in the caudate nucleus and rostral basal forebrain. For both regions, most synchronogenic sites did not produce descending inhibition of dorsal horn neurons. The significance of these findings in relation to descending inhibition from other brain regions and stimulation-produced analgesia is discussed.

Limbic and other Forebrain Mechanisms in Sleep Induction and Behavioral Inhibition

This chapter analyzes the limbic and other forebrain mechanisms in sleep induction and behavioral inhibition. Upon an EEG background characterized by low voltage fast activity, the effects of stimulating various basal forebrain sites with concentric stereotaxically placed bipolar electrodes were observed. Cortical EEG synchronization is of interest to the behavioral physiologist because it is characteristic of the spontaneously occurring cortical spindle pattern associated with sleep and other states of central nervous system suppression. In an evaluation of other brain stimulation studies, the attention of the chapter is drawn to the preoptic-basal forebrain area, in which there appeared to exist potent suppressor mechanisms affecting a variety of peripheral functions. In addition, several other mechanisms may exist which would be reflected in the EEG and perhaps also in the animal's behavior. More anteriorally located hypothalamic zones produced generalized somatomotor suppression and parasympathetic responses to stimulation, and to these areas was ascribed the term ‘trophotropic zone.’