Search

Introduction Superior cognitive performance in older adults may reflect underlying resistance to age‐associated neurodegeneration. While elevated amyloid β (Aβ) deposition (Aβ+) has been associated with increased cortical atrophy, it remains unknown whether “SuperAgers” may be protected from Aβ‐associated neurodegeneration. Methods Neuropsychologically defined SuperAgers (n = 172) and cognitively normal for age (n = 172) older adults from the Australian Imaging, Biomarkers and Lifestyle study were case matched. Rates of cortical atrophy over 8 years were examined by SuperAger classification and Aβ status. Results Of the case‐matched SuperAgers and cognitively normal for age older adults, 40.7% and 40.1%, respectively, were Aβ+. Rates of age‐ and Aβ‐associated atrophy did not differ between the groups on any measure. Aβ− individuals displayed the slowest rates of atrophy. Discussion Maintenance of superior memory in late life does not reflect resistance to age‐ or Aβ‐associated atrophy. However, those individuals who reached old age without cognitive impairment nor elevated Aβ deposition (i.e. Aβ−) displayed reduced rates of cortical atrophy.

Progressive cell loss is observed in the striatum, cerebral cortex, thalamus, hypothalamus, subthalamic nucleus and hippocampus in Huntington disease. In the striatum, dopamine-responsive medium spiny neurons are preferentially lost. Clinical features include involuntary movements, gait and orofacial impairments in addition to cognitive deficits and psychosis, anxiety and mood disorders. We utilized the Cre-LoxP system to generate mutant mice with selective postnatal ablation of D1 dopamine receptor-expressing striatal neurons to determine which elements of the complex Huntington disease phenotype relate to loss of this neuronal subpopulation. Mutant mice had reduced body weight, locomotor slowing, reduced rearing, ataxia, a short stride length wide-based erratic gait, impairment in orofacial movements and displayed haloperidol-suppressible tic-like movements. The mutation was associated with an anxiolytic profile. Mutant mice had significant striatal-specific atrophy and astrogliosis. D1-expressing cell number was reduced throughout the rostrocaudal extent of the dorsal striatum consistent with partial destruction of the striatonigral pathway. Additional striatal changes included up-regulated D2 and enkephalin mRNA, and an increased density of D2 and preproenkephalin-expressing projection neurons, and striatal neuropeptide Y and cholinergic interneurons. These data suggest that striatal D1-cell-ablation alone may account for the involuntary movements and locomotor, balance and orofacial deficits seen not only in HD but also in HD phenocopy syndromes with striatal atrophy. Therapeutic strategies would therefore need to target striatal D1 cells to ameliorate deficits especially when the clinical presentation is dominated by a bradykinetic/ataxic phenotype with involuntary movements.

Transgenic R6/1 mice incorporate a human genomic fragment containing promoter elements exon 1 and a portion of intron 2 of the Huntingtin gene responsible for Huntington's disease. They develop late-onset neurological deficits in a manner similar to the motor abnormalities of the disorder. As essential fatty acids are phospholipid components of cell membranes which may influence cell death and movement disorder phenotype, R6/1 and normal mice were randomised to receive a mixture of essential fatty acids or placebo on alternate days throughout life. Over mid-adulthood, topographical assessment of behaviour revealed R6/1 transgenics to evidence progressive shortening of stride length, with progressive reductions in locomotion, elements of rearing, sniffing, sifting and chewing, and an increase in grooming. These deficits were either not evident or materially diminished in R6/1 transgenics receiving essential fatty acids. R6/1 transgenics also showed reductions in body weight and in brain dopamine D1-like and D2-like quantitative receptor autoradiography which were unaltered by essential fatty acids. These findings indicate that early and sustained treatment with essential fatty acids are able to protect against motor deficits in R6/1 transgenic mice expressing exon 1 and a portion of intron 2 of the Huntingtin gene, and suggest that essential fatty acids may have therapeutic potential in Huntington's disease. © 2002 IBRO. Published by Elsevier Science Ltd. All rights reserved.

We have cloned and characterized a novel murine DNA-binding protein Desrt, with a motif characteristic of the ARID (A-T rich interaction domain) family of transcription factors. The Desrt gene encodes an 83-kD protein that is shown to bind DNA and is widely expressed in adult tissues. To examine the in vivo function of Desrt, we have generated mice with a targeted mutation in the ARID domain of Desrt. Homozygous mutants have reduced viability, pronounced growth retardation, and a high incidence of abnormalities of the female and male reproductive organs including cryptorchidism. This may thus serve as a model to dissect the mechanisms involved in the development of the reproductive tract including testicular descent. Gene-targeted mice also display a reduction in the thickness of the zona reticularis of the adrenal gland and transient aberrations of the T and B cell compartments of primary lymphoid organs. These data show that this novel DNA-binding protein, Desrt, has a nonredundant function during growth and in the development of the reproductive system.

After injury to the substantia nigra pars compacta (SNpc), remaining neurons sprout to ensure normal dopamine delivery to the striatum. The consequent striatal reinnervation is highly regulated, with remaining cells sprouting so that density of dopamine terminals returns to normal. Sprouting as a result of injury is accompanied by a strong glial response; however, it is difficult to know whether this response is as a result of the injury or whether it is aiding in the sprouting. The two cytokines interleukin-1 (IL-1) and interleukin-6 (IL-6) are important modulators of the glia response. This study demonstrates their role in regulating the sprouting of dopaminergic neurons and the associated glia response as a means to examine the role of glia in sprouting. Sprouting was induced by 6-hydroxydopamine lesions of the SNpc and by haloperidol treatment (in the absence of injury). In wild-type animals, sprouting in association with microglial and astrocyte proliferation followed partial lesions of the SNpc and haloperidol treatment. Neither treatment evoked sprouting or glia proliferation in the type I IL-1 receptor-deficient mice, whereas in IL-6-deficient mice, both treatments resulted in glial proliferation but not sprouting. We conclude that IL-1 plays a role in modulating glia proliferation and thereby guidance and trophic factors for new fibers, whereas IL-6 may be important in triggering the outgrowth of new fibers. This study demonstrates that these cytokines play an important role in plasticity and regeneration that is separate from the inflammatory response associated with brain injury.

A novel system was used to assess the role of D1-like dopamine receptors in distinct topographies of orofacial movements in mice with congenic D1A receptor knockout. Under spontaneous conditions, vertical jaw movements in wildtypes declined with time at a rate that was reduced in D1A mutants, while horizontal jaw movements emerged progressively in wildtypes but not in D1A mutants; tongue protrusions were absent in D1A mutants, while incisor chattering was initially reduced in D1A mutants but rose subsequently to reach the level of wildtypes. D1A receptors exert a topographically specific role in regulating individual spontaneous orofacial movements, and these involve interactions with psychomotor processes which 'sculpt' behavioural change over time. The anomalous D1-like agonist SK&F 83959, which fails to stimulate, and indeed inhibits the stimulation of adenylyl cyclase induced by dopamine, readily stimulated vertical jaw movements, tongue protrusions and incisor chattering, and these response topographies were absent in D1A mutants. These results suggest that D1A receptors may exert some form of permissive role over orofacial topographies initiated via a novel, putative D1-like site not linked to adenylyl cyclase, or that some D1A receptors might be coupled to a transduction system other than adenylyl cyclase. © 2002 Elsevier Science Ltd. All rights reserved.

Neuronal nicotinic acetylcholine receptors are ligand-gated ion channels that subserve a range of functions in the brain and peripheral nervous system. They are pentamers variously composed of a (a2-at0) and/3 subunits (beta2-beta4). Pharmacological and ligand-binding studies have shown that the different subunits vary in their distribution and channel properties, but precise delineation of the in vivo function of individual subunits has been hampered by lack of subunit-specific antagonists. The development of transgenic mice with targeted deletions of specific subunits (knockout mice) or mutations in critical receptor domains (knockin mice) has extended understanding of nicotinic receptors, revealing that some subunits are necessary for viability, whereas others mediate modulatory effects on learning and memory, locomotion, anxiety, nociception, dopaminergic neurotransmission, seizure threshold, development of the visual system and autonomic function. In some cases, studies of transgenic mice have confirmed expectations derived from pharmacological and expression studies, but in other cases, compensation by related subunits has revealed a degree of functional redundancy not predicted by previous approaches.

This study demonstrates that pharmacological manipulation of the dopamine (DA) receptors can modulate the size of the axonal tree of substantia nigra pars compacta (SNpc) neurons in mice. Pharmacological blockade or genetic ablation of the D2 receptor (D2R) resulted in sprouting of DA SNpc neurons whereas treatment with a D2 agonist resulted in pruning of the terminal arbor of these neurons. Agents such as cocaine, that indirectly stimulate D2R, also resulted in reduced terminal arbor. Specific D1 agonists or antagonists had no effect on the density of DA terminals in the striatum. We conclude that the D2 receptor has a central role in regulating the size of the terminal arbor of nigrostriatal neurons. These findings have implications relating to the use of dopaminergic agonists in the management of Parkinson's disease and in controlling plasticity following injury, loss or transplantation of DA neurons.

Previously we described the extent of sprouting that axons of the rat substantia nigra pars compacta (SNpc) undergo to grow new synapses and re-innervate the dorsal striatum 16 weeks after partial lesions. Here we provide insights into the timing of events related to the re-innervation of the dorsal striatum by regenerating dopaminergic nigrostriatal axons over a 104-week period after partial SNpc lesioning. Density of dopamine transporter and tyrosine hydroxylase immunoreactive axonal varicosities (terminals) decreased up to 80% 4 weeks after lesioning but returned to normal by 16 weeks, unless SNpc lesions were greater than 75%. Neuronal tracer injections into the SNpc revealed a 119% increase in axon fibres (4 mm rostral to the SNpc) along the medial forebrain bundle 4 weeks after lesioning. SNpc cells underwent phenotypic changes. Four weeks after lesioning the proportion of SNpc neurons that expressed tyrosine hydroxylase fell from 90% to 38% but returned to 78% by 32 weeks. We discuss these phenotype changes in the context of neurogenesis. Significant reductions in dopamine levels in rats with medium (30-75%) lesions returned to normal by 16 weeks whereas recovery was not observed if lesions were larger than 75%. Finally, rotational behaviour of animals in response to amphetamine was examined. The clear rightward turning bias observed after 2 weeks recovered by 16 weeks in animals with medium (30-75%) lesions but was still present when lesions were larger. These studies provide insights into the processes that regulate sprouting responses in the central nervous system following injury.

Recent studies suggest that the dorsal raphe nucleus (DRN) of the brainstem contains several subdivisions that differ both anatomically and neurochemically. The present study examined whether variation of c-Fos expression across the 24-hour light-dark cycle may also be different in these subdivisions. Animals were kept on a 12:12 light-dark cycle, were perfused at seven different time points, and brain sections were processed by using c-Fos immunocytochemistry. At all coronal levels of the DRN, c-Fos expression reached a peak 1 hour after the light-dark transition (lights-off) and reached its lowest levels in the middle of the light period. In contrast to the light-dark transition, c-Fos levels did not change significantly after the dark-light transition (lights-on). One-way analysis of variance (ANOVA) revealed that the diurnal variation of c-Fos expression was highly significant in the caudal ventral DRN. Similar variation in c-Fos expression also was observed in the other DRN subdivisions, but this variation appeared to gradually diminish in the caudal-to-rostral and ventromedial-to-dorsomedial directions. Double-label immunocytochemistry revealed that, 1 hour after lights-off, only 11% of c-Fos-positive neurons in the caudal ventral DRN were serotonin (5-HT)-immunoreactive. These results suggest that DRN subdivisions may differ functionally with regard to the diurnal cycle, and that these differences may be reflected in the activity of nonserotonergic cells in the DRN. © 2001 Wiley-Liss, Inc.

Following partial substantia nigra lesions, remaining dopaminergic neurones sprout, returning terminal density in the dorsal striatum to normal by 16 weeks. This suggests regeneration and maintenance of terminal density is regulated to release appropriate levels of dopamine. This study examined the structure and function of these reinnervated terminals, defining characteristics of dopamine uptake and release, density and affinity of the dopamine transporter (DAT) and ultrastructural morphology of dopamine terminals in the reinnervated dorsal striatum. Finally, rotational behaviour of animals in response to amphetamine was examined 4 and 16 weeks after substantia nigra pars compacta (SNpc) lesions. Dopamine transport was markedly reduced 16 weeks after lesioning along with reduced density and affinity of DAT. Rate of dopamine release and peak concentration, measured electrochemically, was similar in lesioned and control animals, while clearance was prolonged after lesioning. Ultrastructurally, terminals after lesioning were morphologically distinct, having increased bouton size, vesicle number and mitochondria, and more proximal contacts on postsynaptic cells. After 4 weeks, tendency to rotate in response to amphetamine was proportional to lesion size. By 16 weeks, rotational behaviour returned to near normal in animals where lesions were less than 70%, although some animals demonstrated unusual rotational patterns at the beginning and end of the amphetamine effect. Together, these changes indicate that sprouted terminals are well compensated for dopamine release but that transport mechanisms are functionally impaired. We discuss these results in terms of implications for dyskinesia and other behavioural states.

Adenosine A(2a) receptor knockout mice (A(2a)R k/o) have been characterised as hypertensive, aggressive, anxious and hypoalgesic [12]. Thus, the present study was designed to investigate markers of glutamatergic transmission in specific brain nuclei associated with autonomic regulation. Visualisation of alpha-amino-3-hydroxy-5-methylisoxasole-4-propionic acid binding sites in the brains of A(2a)R k/o mice was achieved by utilising quantitative receptor autoradiography with (S)-[3H]-5-fluorowillardiine ([3H]FW:10 nM) on slide-mounted sections of mouse-brain. [3H]FW binding significantly increased in the nucleus tractus solitarius and area postrema of A(2a)R k/o mice compared with wildtype CD-1 mice. In other autonomic nuclei examined, binding was unchanged between wildtype and knockout mice. The present study suggests that glutamatergic neurotransmission within certain neural pathways involved in autonomic and motor control is altered in the brains of A(2a)R k/o mice. (C) 2000 Elsevier Science Ireland Ltd.

The present study was designed to assess whether adenosine A(2a) receptor knockout mice exhibit altered purine utilisation in brain nuclei. Specifically, the properties of adenosine transporters and adenosine A1 receptors were characterised in brain membranes and on slide-mounted sections. The B(MAX) for [3H]nitrobenzylthioinosine ([3H]NBTI) binding (adenosine transporter density) was significantly reduced in brainstem membranes of homozygotes (560 +/- 52 fmol/mg protein, n = 5, P < 0.05, Kruskal-Wallis ANOVA) compared to wildtype (1239 +/- 213 fmol/mg protein) and heterozygous mice (1300 +/- 558 fmol/mg protein). Quantitative autoradiography data indicated that [3H]NBTI binding in the medulla oblongata of heterozygous mice was seen to decrease significantly (P < 0.05) in the subpostremal nucleus tractus solitarius (NTS), medial NTS, inferior olive and area postrema (AP). On the other hand, in the homozygous mice a decrease was seen in the medial NTS and AP. In the pons, [3H]1,3-dipropyl-8- cyclopentylxanthine ([3H]DPCPX) (adenosine A1 receptor density) binding increased significantly (P < 0.05, Kruskal-Wallis ANOVA) in the lateral parabrachial nucleus, caudal pontine reticular nucleus and locus coeruleus of homozygotes compared to wildtype. In higher brain centres, [3H]NBTI binding was reduced in the paraventricular thalamic nucleus of both heterozygous and homozygous mice, whereas [3H]DPCPX binding was reduced in the hippocampus and lateral hypothalamus of heterozygotes. In homozygotes, [3H]DPCPX binding in the hippocampus increased compared to wildtype mice. The present study indicates that deletion of the A(2a) receptor may have contributed to region- specific compensatory changes in purine utilisation in brain nuclei associated with autonomic, neuroendocrine and behavioural regulation. (C) 2000 Elsevier Science B.V.

The genetic basis of a number of epilepsy syndromes has been identified but the precise mechanism whereby these mutations produce seizures is unknown. Three mutations of the alpha4 subunit of the neuronal nicotinic acetylcholine receptor (nAChR) have been identified in autosomal dominant nocturnal frontal lobe epilepsy. In vitro studies of two mutations suggest an alteration of receptor function resulting in decreased ion channel current flow. We investigated the response of alpha4 nAChR subunit knockout mice to the gamma-aminobutyric acid (GABA) receptor antagonists; pentylenetetrazole (PTZ) and bicuculline (BIC), the glutamate receptor agonist kainic acid (KA), the glycine receptor antagonist strychnine and the K+ channel blocker 4-aminopyridine (4-AP). Mutant (Mt) mice had a greater sensitivity to PTZ and BIC, with an increase in major motor seizures and seizure-related deaths. Furthermore, Mt mice were more sensitive to KA and strychnine, but the effects were much smaller compared to those seen with the GABA receptor antagonists. Paradoxically, Mt mice appeared to be relatively protected from 4-AP-induced major motor seizures and death. The results show that a functional deletion of the alpha4 nAChR subunit in vivo is associated with a major increase in sensitivity to GABA receptor blockers. © 2002 Elsevier Science Ltd. All rights reserved.

Abnormal dopamine (DA) transmission occurs in many pathological conditions, including drug addiction. Previously, we showed DA D2 receptor (D2R) activation results in pruning of the axonal arbour of DA neurones that innervate the dorsal striatum. Thus, we hypothesised that long-term D2R stimulation through drugs of addiction should cause arbour pruning of neurones that innervate the ventral striatum and thus reduce DA release and contribute to craving. If so, D2R blockade should return these arbours to normal size and may overcome craving. We show that long-term treatment with a D2R antagonist (haloperidol) reverses behavioural and anatomical effects of cocaine dependence in mice, including relapse. This change in arbour size reflects new synapse formation and our data suggest this must occur in the presence of increased DA activity to reverse cocaine-seeking behaviour. These findings hold significant implications for the understanding and treatment of cocaine addiction. © 2005 Elsevier Inc. All rights reserved.

Neurochemical changes were examined in dopamine D1 receptor knockout (D1-/-), dopamine D3 receptor knockout (D3-/-) and dopamine D1/D3 receptor double knockout (D1-/-D3-/-) mice. The level of dopamine D1- and D2-like receptors and gamma-aminobutyric acid (GABAA) receptor was assessed by ligand autoradiography and dopamine D1- and D2 receptor, enkephalin, dynorphin and substance P transcripts measured by in situ hybridization. D1-/- mice had normal GABAA receptor levels, reduced dynorphin and substance P, and increased enkephalin mRNA and dopamine D2-like binding. D1-/-D3-/- mice evidenced decreased dynorphin and substance P but normal enkephalin expression, whereas dopamine D2-like and GABAA receptor binding were increased. Major changes occur in substance P and dynorphin expression in D1-/- mice and these changes are unaffected by loss of dopamine D3 receptors. Upregulated dopamine D2-like binding and enkephalin in D1-/- mice may be due to decreased dopamine turnover. Upregulated enkephalin in D1-/- mice is dependent on functional dopamine D3 receptors. © 2003 Elsevier Science B.V. All rights reserved.

Autosomal Dominant Nocturnal Frontal Lobe Epilepsy (ADNFLE) is associated in some kindreds with mutations in the genes encoding the alpha4 or beta2 subunits of the neuronal nicotinic acetylcholine receptor (nAChR). Functional characterisation of the described ADNFLE mutations in oocyte preparations has produced conflicting results, with some studies suggesting hypofunction but others showing increased ligand sensitivity or delayed desensitisation. Knockout mice were studied to investigate extreme hypofunction of alpha4 nAChRs in vivo. Mutant (Mt) and control mice underwent epidural electroencephalographic (EEG) recording for 2 h in the untreated state and for 1 h following administration of the gamma-amino butyric acid (GABA) antagonist, pentylenetetrazole (PTZ, 80 mg/kg). No spontaneous seizures occurred and no EEG differences were observed between the genotypes in drug naive mice. Following PTZ, however, Mt mice showed markedly increased mortality compared to controls (85 vs 30%, P<0.001). Mts also had a greater number of generalised clonic seizures in the first 40 min following injection. In the same period, the EEGs of Mt mice showed an excess of spikes (P=0.033), multi-spike complexes (P=0.002) and continuous fast activity (P=0.017) compared to controls. These findings demonstrate that intact alpha4 nAChR subunits provide significant in vivo protection against the proconvulsant effects of GABA antagonism. © 2003 Elsevier Science Ltd. All rights reserved.