Locus coeruleus projections to cortex: Topography, morphology and collateralization

The relationship between individual cells of origin within the nucleus locus coeruleus (LC) and the geometry and distribution of terminal fields in cortex was examined in the albino rat. Computer-assisted 3-dimensional reconstructions of the Nissl-stained LC allowed the characterization of the spatial distribution of LC cells. Similar reconstructions of the distributions of labelled cells following cortical injections of horseradish peroxidase were created. Comparisons of such reconstructions revealed that LC cells projecting to cortex were distributed throughout the compact dorsal LC. These cells were predominantly medium sized multipolar cells. Significant labelling of other morphological sub-populations of LC did not occur following cortical injections. Simultaneous injections of multiple fluorescent retrograde tracers into different cortical regions allowed the characterization of LC axon collateralization in cortex. Individual LC cells innervate functionally and cytoarchitectonically distinct cortical regions simultaneously. LC cells arborize more extensively in the anterior-to-posterior axis of cortex and exhibit relatively minimal medial-to-lateral collateralization. Individual LC cells were also shown to innervate both superficial and deep layers of a cortical region.     

Origins of multisynaptic projections from the basal ganglia to the forelimb region of the ventral premotor cortex in macaque monkeys

The ventral premotor cortex (PMv), occupying the ventral aspect of area 6 in the frontal lobe, has been implicated in action planning and execution based on visual signals. Although the PMv has been characterized by cortico‐cortical connections with specific subregions of the parietal and prefrontal cortical areas, a topographical input/output organization between the PMv and the basal ganglia (BG) still remains elusive. In the present study, retrograde transneuronal labelling with the rabies virus was employed to identify the origins of multisynaptic projections from the BG to the PMv. The virus was injected into the forelimb region of the PMv, identified in the ventral aspect of the genu of the arcuate sulcus, in macaque monkeys. The survival time after the virus injection was set to allow either the second‐ or third‐order neuron labelling across two or three synapses. The second‐order neurons were observed in the ventral portion (primary motor territory) and the caudodorsal portion (higher‐order motor territory) of the internal segment of the globus pallidus. Subsequently, the third‐order neurons were distributed in the putamen caudal to the anterior commissure, including both the primary and the higher‐order motor territories, and in the ventral striatum (limbic territory). In addition, they were found in the dorsolateral portion (motor territory) and ventromedial portion (limbic territory) of the subthalamic nucleus, and in the external segment of the globus pallidus including both the limbic and motor territories. These findings indicate that the PMv receives diverse signals from the primary motor, higher‐order motor and limbic territories of the BG.     

Cortical projections of posterior parietal cortex in owl monkeys.

Efferent cortical projections of posterior parietal cortex were determined by degeneration and autoradiographic methods in owl monkeys. Intraregional connections were to the immediate surround of the injection or lesion site, and to distinct foci within the posterior parietal region. The extraregional ipsilateral connections were with (1) previously established subdivisions of visual association cortex (the Dorsomedial Area, the Medial Area, the Dorsolateral Area, and the Middle Temporal Area), (2) other locations in caudal neocortex, and (3) frontal cortex. The callosal projections were to separate foci in posterior parietal cortex of the contralateral cerebral hemisphere. The separate foci of both ipsilateral and contralateral terminations in posterior parietal cortex raise the possibility that this region contains more than one functional subdivision. The connections with visual association cortex suggest a role for parietal cortex in visual behavior. Other foci in caudal neocortex indicate the possible locations of additional subdivisions of association cortex.     

Interhemispheric nigrothalamic projections and behavioral recovery following turning behavior induced by unilateral peripheral sensory and motor restriction

We investigated the relationship between unilateral peripheral lesions plus partial sensory deprivation and interhemispheric nigrothalamic projections. Sensory-motor asymmetries were induced in rats by unilateral ligature of sensory and motor nerves of the forelimbs and hind limbs and partial sensory deprivation (cutting the vibrissae unilaterally and suturing one eyelid). This operation resulted in spontaneous turning which was partially compensated for within the first 5 postoperative days. Sixteen days after the surgery, animals were implanted with horseradish peroxidase in the ventrobasal thalamus of one hemisphere. Brains were processed by the tetramethylbenzidine procedure. Microscopical analysis revealed interhemispheric nigrothalamic projections from the substantia nigra situated ipsilateral but not contralateral to the denervated limbs. The results are interpreted in terms of a reorganization (sprouting) of interhemispheric nigrothalamic projections in response to unilateral peripheral lesions. The lesion-induced behavioral asymmetry and its partial compensation may be one of the determinants of the observed neuronal plasticity.     

Intraputamenal infusion of GDNF in aged rhesus monkeys: distribution and dopaminergic effects

Site-specific delivery of trophic factors in the brain may be important for achieving therapeutic efficacy without unwanted side effects. This study evaluated the site-specific infusion of glial cell line-derived neurotrophic factor (GDNF) into the right putamen of aged rhesus monkeys. After 4 weeks of continuous infusion at a rate of 22.5 microg/day, GDNF had diffused up to 11 mm from the catheter openings in the putamen into the rostral putamen, internal capsule, external capsule, caudate nucleus, and globus pallidus. Anisotropic flow along the external capsule tracts carried GDNF into the anterior amygdaloid area. Backflow of GDNF along the catheter track from the frontal cortex infiltrated juxtaposed corpus callosal and cortical tissue. GDNF was carried by retrograde transport to dopamine neurons in the ipsilateral substantia nigra, stimulating an 18% increase in the number of tyrosine hydroxylase (TH)-positive dopamine neurons and a 28% increase in dopamine neuron perikaryal size. Also, TH-positive fiber density was increased in the ipsilateral globus pallidus, caudate nucleus, and putamen. Anatomic effects from GDNF stimulation of the dopaminergic system were restricted to the ipsilateral hemisphere. Retrograde GDNF labeling was also present in a few TH-positive neurons in the locus coeruleus and a large cluster of TH-negative neurons in the ventral anterior thalamus. Anterograde transport of GDNF was evident in axons in the pyramidal tract from the cerebral peduncle to the caudal spinal cord. Tissue injury from the intraparenchymal catheter and continuous infusion was confined primarily to a narrow zone surrounding the track and was mild to moderate in severity.     

Topography of projections from the medial prefrontal cortex to the amygdala in the rat

The projections from the rat medial prefrontal cortex to the amygdaloid complex were investigated using retrograde transport of fluorescent dyes and anterograde transport of horseradish peroxidase-WGA. The ventral anterior cingulate, prelimbic, infralimbic and medial orbital areas and the taenia tecta were found to project to the amygdaloid complex. The projections from the prelimbic area arose bilaterally. The medial orbital, prelimbic and anterior cingulate areas send convergent projections to the basolateral nucleus. The prelimbic area has additional projections to the posterolateral cortical nucleus and amygdalo-hippocampal area. The infralimbic area does not project to the basolateral nucleus and cortico-amygdaloid projections from this area are focussed on the anterior cortical nucleus and the anterior amygdaloid area. Both prelimbic and infralimbic areas project to an area situated between the central, medial and basomedial nuclei. Based on similar projections, this area appears to be a caudal continuation of the anterior amygdaloid area. The results indicate that the medial prefrontal component of the "basolateral limbic circuit" is restricted to the anterior cingulate and prelimbic areas. No evidence was obtained to support the existence of a medial prefronto-amygdaloid component of the "visceral forebrain".     

Distribution of nigrothalamic projections in the dog.

The distribution of nigrothalamic projections was studied in the dog by using the autoradiographic tracing method. On the basis of a systematic series of tritiated amino acid injections into different portions of the substantia nigra, we found that the rostral three-fourths of the substantia nigra pars reticulata (SNr) gives rise to widespread thalamic projections. The nigrothalamic label occupied a longitudinal band extending from rostral ventral anterior nucleus (VA) through to caudal mediodorsal nucleus (MD). In the dog, VA is histochemically identified as an acetylthiocholinesterase (AChE)-negative region and is distinct from the adjacent ventral lateral nuclei which stain positively for AChE. In rostral thalamus, the dense autoradiographic label was observed in rostral VA within the AchE-negative region lying alongside the mammillothalamic tract (MT). The adjacent AChE-positive ventral lateral nuclei did not contain autoradiographic label. In addition, homogeneously distributed silver grains were observed throughout the ventromedial nucleus (VM) bilaterally. More caudally, as the ventral lateral thalamic compartment emerges, label was also observed within the internal medullary lamina region, including the paralaminar portion of VA, the central lateral nucleus (CL), and the paralaminar portion of MD. Finally, in caudal thalamus, the central portion of MD, as well as the parafascicular nucleus (Pf), contained autoradiographic label. The overall nigrothalamic distribution observed in the dog was similar to the distribution of nigrothalamic projections in monkeys with one exception. Unlike that of primates, the distribution of nigral efferents is to the whole extent of VM in the dog as in other non-primate species. Overall, we found that nigral efferents primarily project to three main thalamic targets: the VA/MD region, VM, and the internal medullary lamina region, which includes dorsal CL and paralaminar VA and MD. We propose that these three nigrothalamic territories may constitute critical links subserving different functional channels.     

Antagonism of NMDA receptors but not AMPA/kainate receptors blocks bursting in dopaminergic neurons induced by electrical stimulation of the prefrontal cortex

Summary Evidence suggests that the prefrontal cortex (PFC) plays an important role in the burst activity of midbrain dopaminergic (DA) neurons. In particular, electrical stimulation of the PFC elicits patterns of activity in DA neurons, closely time-locked to the stimulation, which resemble natural bursts. Given that natural bursts are produced by the activity of excitatory amino acid (EAA)-ergic afferents, if PFC-induced time-locked bursts are homologues of natural bursts, EAA antagonists should attenuate them. Hence, the NMDA (N-methy1-D-aspartate) antagonist CPP (3-((±)-2-carboxypiperazin-4-yl)propyl-1-phosphonic acid) and the AMPA (D,L--amino-3-hydroxy-5-methyl-4-isoxalone propionic acid)/kainate antagonist CNQX (6-cyano-7-nitroquinoxaline-2,3-dione) were applied by iontophoresis to DA neurons exhibiting time-locked bursts during PFC stimulation. CPP produced a significant reduction in time-locked bursting. In contrast, CNQX (at currents which antagonised AMPA responses) did not. These effects of CPP and CNQX on time-locked bursting mirror the effects previously reported for these drugs on natural bursting. Since natural bursting and bursting induced by PFC stimulation are both blocked selectively by CPP, the present results increase the degree of analogy between the two burst phenomena, thereby adding extra support to the contention that the cortex is involved in producing the natural bursting in DA neurons.     

Diminution of dopaminergic neurons in the substantia nigra of sporadic amyotrophic lateral sclerosis

The substantia nigra was examined immunohistochemically using the antibody to tyrosine hydroxylase in 15 patients with sporadic amyotrophic lateral sclerosis (ALS). The number of dopaminergic neurons was diminished in the substantia nigra of seven cases. The diminution was not related to the age, duration of the illness or use of respirators. Supranuclear ophthalmoplegia developed in four and dementia in three out of seven patients with reduction of nigral dopaminergic neurons. In addition, five out of the seven patients developed respiratory failure within 2 years after the onset of the illness. The nigral dopaminergic system may be involved in rapidly progressive ALS patients with supranuclear ophthalmoplegia and/or dementia.     

Collateral projections from the substantia nigra to the cingulate cortex and striatum in the rat

After injecting a retrograde tracer into the posterior cingulate cortex, labeled neurons were found only in the substantia nigra pars compacta, leaving neurons in the ventral tegmental area totally unlabeled. The existence of collateral nigral projections to the cingulate cortex and striatum was clearly established using the fluorescent retrograde double-labeling technique. This constitutes a neuroanatomical substrate for psychotic symptoms expressed by a subpopulation of parkinsonian patients.     

Collateral projections from the rat hippocampal formation to the lateral and medial prefrontal cortex

Projections from the hippocampal formation to the medial prefrontal cortex are well known. In this report we used two retrogradely transported tracers to show that a small but significant subpopulation of pyramidal neurons in area CA1 and subiculum of the hippocampal formation projects to the lateral prefrontal cortex. About half of these neurons also possess collateral projections to the medial prefrontal cortex. The neurons projecting only to the lateral PFC are found in the intermediate hippocampal formation and in the most ventral part of the temporal subdivision. On the other hand, most of the neurons projecting to the medial prefrontal cortex only are present in the temporal and ventral intermediate hippocampal formation, and their number decreases in the dorsal intermediate subdivision. The distribution of neurons having collateral projections is comparable to that of neurons projecting to the medial prefrontal cortex only. In view of proposed functional differences between the septal one-third and the temporal two-third of the hippocampal formation, it is of interest that the neurons projecting to the prefrontal cortex are only present in the temporal two-thirds. Hippocampus 7:397–402, 1997. © 1997 Wiley-Liss, Inc.     

Regional concentrations of noradrenaline and dopamine in the frontal cortex of the rat: dopaminergic innervation of the prefrontal subareas and lateralization of prefrontal dopamine

Catecholamine levels in the two subareas of the prefrontal cortex and in one non-prefrontal region of the rat frontal lobe were measured radioenzymatically. In contrast with noradrenaline (NA), the distribution of dopamine (DA) in the frontal lobe is markedly heterogeneous. DA levels of the orbitofrontal and medial prefrontal subarea are, respectively, 3 and 4 times higher than those of a non-prefrontal region of the frontal lobe, confirming the expectation of neuroanatomical findings. Furthermore, it appears that at the population level, DA levels of the medial prefrontal subarea are lateralized, the left hemisphere being significantly higher than the right hemisphere.     

Ganglioside interactions with the dopaminergic system of rats

The effects of ganglioside treatment on changes in dopaminergic function following 6-hydroxydopamine (6-OHDA) or repeated exposure to haloperidol were studied in male Fischer-344 rats. Rats were injected sc with 30 mg/kg of a mixed ganglioside preparation (GM) at the time of the surgery and for 13 days after receiving an intranigral injection of 6-OHDA. GM treatment attenuated 6-OHDA depletion of striatal dopamine (DA) and DOPAC. Another group of rats was implanted with chronic indwelling cannulas in the lateral cerebroventricles at the time of 6-OHDA administration into the substantia nigra. Daily intraventricular injection of 25 or 50 micrograms GM attenuated depletions of striatal DA and DOPAC. A separate experiment sought to determine the effects of GM1 on the development of receptor supersensitivity produced by repeated exposure to a dopamine receptor antagonist. Rats were injected sc with 1 mg/kg haloperidol for 8 or for 16 days; some rats were coadministered 20 mg/kg GM1 sc. Four days after the last dose, the rats were challenged with 1 mg/kg apomorphine, and activity was counted for 60 min. Treatment with GM1 decreased the behavioral supersensitivity to apomorphine induced by repeated exposure to haloperidol. These experiments suggest that treatment with GM can have a protective effect against 6-OHDA-induced depletion of dopamine if treatment with GM begins at the time of lesioning. These studies also support receptor binding data from other laboratories indicating that treatment with GM1 can affect up-regulation of dopamine receptors.     

Differential subsensitivity of dopaminergic and neostriatal neurons to apomorphine with long-term treatment

The apomorphine-induced inhibition of dopaminergic neurons in the substantia nigra of the rat was significantly attenuated following 2 daily injections of 0.05, 0.5 or 2.0 mg/kg apomorphine for 5 consecutive days. In fact, many of these neurons responded with an increase in firing rate whiich was never observed in control animals. Neostriatal neurons, on the other hand, decreased their sensitivity to apomorphine only after long-term treatment with 0.5 or 2.0 mg/kg. Multiple injections of the low dose actually potentiated the apomorphine-induced inhibition in the neostriatum. These results, which are consistent with the differential sensitivity of dopaminergic and neostriatal neurons to acute apormorphine, suggest that the subsensitivity of pre- and postsynaptic dopamine receptors produced by long-term apomorphine treatment is dose-dependent.     

Cortical projections of the dorsolateral visual area in owl monkeys: the prestriate relay to inferior temporal cortex

The dorsolateral visual area (DL) is one of a number of visual areas that have been defined by electrophysiological mapping procedures and cortical architecture in the extrastriate cortex of owl monkeys. The projections of DL were determined by the intra-axonal transport of 3H-proline, 3H-acetyl-wheat germ agglutinin, and horseradish peroxidase after cortical injections. The major ipsilateral projection of DL defined a new subdivision of the visual cortex in owl monkeys, the caudal inferior temporal cortex. Single injections in DL sometimes produced label in two separate regions in the caudal inferior temporal cortex, suggesting that functional subdivisions exist in this projection zone. Other targets of DL included the region of the frontal eye fields, the dorsomedial visual area, the dorsointermediate visual area (DI), a region of the cortex rostral to DI which we call the temporoparietal cortex, and possibly the ventral (V) and posterior parietal areas. A major feedback projection of DL was to V-II. Projections from DL to V-II and the dorsomedial visual area were roughly retinotopic. Projections from DL to the contralateral cerebral hemisphere were to DL and the inferior temporal cortex. Overall, the results support the concept that a major relay of visual information proceeds from V-I to V-II to DL and then to the inferior temporal cortex. In addition, similarities in connection patterns of DL in owl monkeys and V4 in macaque monkeys suggest that DL and much or all of V4 are homologous.     

Nigrothalamic projections and nigrothalamocortical pathway to the medial agranular cortex in the rat: Single- and double-labeling light and electron microscopic studies

Although the rat medial agranular cortex (AGm) has been implicated in a variety of motor functions, the source of the afferents impinging upon thalamic neurons projecting to the AGm is not directly known. The main purpose of this study was to determine whether the AGm is a major recipient of the nigrothalamocortical pathway. This issue was addressed by two sets of experiments. First, the organization of the nigrothalamic projections was studied by light and electron microscopy following injections of the anterograde tracer Phaseolus vulgaris-leucoagglutinin (PHA-L) into the pars reticulata of the substantia nigra (SNR). The major finding of this study was the disclosure of a heretofore unknown projection to the rostromedial part of the ventral anterior-ventral lateral complex (VAL). This projection originates exclusively from the ventral portion of the SNR and is comparable in strength to the well-known nigrothalamic projection to the ventromedial nucleus (VM). Electron microscopic examination revealed differences in the synaptic organization of nigral terminals in the VAL and the VM. A large proportion of the labeled terminals in the VAL was involved in axosomatic synapses, whereas, in the VM, the axosomatic synapses were rare, and 67% of nigral terminals were found in contact with thin dendrites. To assess a possible disynaptic nigrothalamocortical pathway to the AGm, a double-labeling strategy combining PHA-L injections in the SNR and pressure injections of the retrograde tracer, cholera toxin subunit B (CTB) in the AGm was employed. The greatest density of CTB-labeled neurons was found in the rostral and central portion of the VAL, coincident with the nigrothalamic labeling originating from the ventral SNR. Electron microscopic analysis confirmed that some of the PHA-L-labeled terminals established synaptic contacts with the CTB-labeled cell bodies and large dendrites. In conclusion, our findings indicate that there exist two different nigrothalamocortical pathways through the motor thalamus in the rat. The SNR-VAL-AGm cortical projection may play a role in oculomotor functions, whereas the SNR-VM-cortical pathway has been implicated in arousal mechanisms. J. Comp. Neurol. 391:506–525, 1998. © 1998 Wiley-Liss, Inc.     

Differential calbindin-immunoreactivity in dopamine neurons projecting to the rat striatal complex

The calcium-binding protein calbindin-D28K is an anatomical marker that has been associated with resistance to neurodegeneration and with the electrophysiological characteristics of neurons. In this study, we compared the presence of calbindin in dopamine neurons projecting to three distinct functional regions of the striatal complex: the striatum, and the core and the shell of the nucleus accumbens. After iontophoretic injections of Fluoro-Gold in the dopaminergic terminal fields, the presence of tyrosine hydroxylase and calbindin were immunohistochemically assessed in the mesencephalon. It was found that the proportion of cells expressing calbindin was highest in the dopamine cells projecting to the core (72%), intermediate in the cells projecting to the shell (51%) and lowest in the cells projecting to the dorsolateral striatum (2.6%). These results do not support the idea that calbindin is a sufficient condition to confer resistance to neurodegeneration because shell-projecting neurons seem the most resistant to it. The present data also raise the question of the role of calbindin in the differences in firing characteristics among dopamine neurons projecting to the striatal complex.     

Age-related declines in nigral neuronal function correlate with motor impairments in rhesus monkeys

Although the role of dopamine dysfunction is well established in Parkinson's disease, the effect of nigrostriatal degeneration on motor performance during normal aging is less well understood. In this study, aged rhesus monkeys (25–27 years old) displayed significant impairments relative to young (3–5 years old) cohorts in motor function as assessed on a fine motor task and home cage activity. Additionally, the clinical motor function of aged monkeys was impaired relative to young monkeys as assessed on a clinical rating scale. Unbiased stereologic measurements of the substantia nigra revealed a significant age-related loss of tyrosine hydroxylase-immunoreactive (TH-ir; 50.3%) and dopamine transporter-immunoreactive (DAT-ir; 33.2%) nigral neurons. The monkeys performance on the fine motor task and on the clinical rating scale was correlated with TH-ir neuronal counts. The number of DAT-ir nigral neurons was correlated with activity and clinical rating scale scores. Our results suggest that age-related motor impairments in nonhuman primates are associated with spontaneous decreases in TH-ir and DAT-ir nigral cells. The correlation of motor deficits with the loss of TH-ir and DAT-ir nigral neurons suggests that aged nonhuman primates may provide a useful model for mimicking changes seen in human aging and early Parkinson's disease. J. Comp. Neurol. 401:253–265, 1998. © 1998 Wiley-Liss, Inc.     

Influences of dopaminergic systems on the blink reflex

The effect of the anti-dopaminergic drug haloperidol (6 mg/day i.m. for 2 days) on the blink reflex elicited by electric stimulation of supraorbital nerves was investigated in 12 adult volunteers. A significant increase in amplitude of the early component (R1) of the reflex was observed. This increase disappeared within 5 days of stopping the drug. Possible neural systems which might be involved in these effects are considered.

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Sommario Su 12 volontari adulti, neurologicamente indenni, sono stati studiati gli effetti indotti dalla somministrazione di un farmaco dopaminolitico (aloperidolo, 6 mg/die × 2 giorni) sul riflesso di ammiccamento (blink reflex). Si è osservato un significativo aumento dell'ampiezza della componente precoce (R1) del riflesso, con un ritorno alla norma entro 5 giorni dalla cessazione della somministrazione del farmaco. Vengono discussi i possibili circuiti nervosi coinvolti negli effetti osservati.

     

Diverse thalamic projections to the prefrontal cortex in the rhesus monkey.

We studied the sources of thalamic projections to prefrontal areas of nine rhesus monkeys with the aid of retrograde tracers (horseradish peroxidase or fluorescent dyes). Our goal was to determine the proportion of labeled neurons contributing to this projection system by the mediodorsal (MD) nucleus compared to those distributed in other thalamic nuclei, and to investigate the relationship of thalamic projections to specific architectonic areas of the prefrontal cortex. We selected areas for study within both the basoventral (areas 11, 12, and ventral 46) and the mediodorsal (areas 32, 14, 46, and 8) prefrontal sectors. This choice was based on our previous studies, which indicate differences in cortical projections to these two distinct architectonic sectors (Barbas, '88; Barbas and Pandya, '89). In addition, for each sector we included areas with different architectonic profiles, which is also relevant to the connectional patterns of the prefrontal cortices. The results showed that MD included a clear majority (over 80%) of all thalamic neurons directed to some prefrontal cortices (areas 11, 46, and 8); it contributed just over half to some others (areas 12 and 32), and less than a third to area 14. Clusters of neurons directed to basoventral and mediodorsal prefrontal areas were largely segregated within MD: the former were found ventrally, the latter dorsally. However, the most striking findings establish a relationship between thalamic origin and laminar definition of the prefrontal target areas. Most thalamic neurons directed to lateral prefrontal cortices, which are characterized by a high degree of laminar definition (areas 46 and 8), originated in the parvicellular and multiform subdivisions of MD, and only a few were found in other nuclei. In contrast, orbital and medial cortices, which have a low degree of laminar differentiation, were targeted by the magnocellular subdivision of MD and by numerous other limbic thalamic nuclei, including the midline and the anterior. Thus topographic specificity in the origin of thalamic projections increased as the laminar definition of the target area increased. Moreover, the rostrocaudal distribution of labeled neurons in MD and the medial pulvinar also differed depending on the degree of the laminar definition of the prefrontal target areas. The rostral parts of MD and the medial pulvinar projected to the eulaminate lateral prefrontal cortices, whereas their caudal parts projected to orbital and medial limbic cortices. Selective destruction of caudal MD is known to disrupt mnemonic processes in both humans and monkeys, suggesting that this thalamic-limbic prefrontal loop may constitute an important pathway for memory.