Publications by authors named "Manfred J Oswald"

14 Publications

  • Page 1 of 1

Repetitive non-invasive prefrontal stimulation reverses neuropathic pain via neural remodelling in mice.

Prog Neurobiol 2021 06 20;201:102009. Epub 2021 Feb 20.

Institute of Pharmacology, Medical Faculty Heidelberg, Heidelberg University, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany. Electronic address:

Chronic neuropathic pain presents a major challenge to pharmacological therapy and neurostimulation-based alternatives are gaining interest. Although invasive and non-invasive motor cortex stimulation has been the focus of several studies, very little is known about the potential of targeting the prefrontal cortex. This study was designed to elucidate the analgesic potential of prefrontal stimulation in a translational context and to uncover the neural underpinnings thereof. Here, we report that non-invasive, repetitive direct anodal current transcranial stimulation (tDCS) of the prefrontal cortex exerted analgesia in mice with neuropathic pain for longer than a week. When applied at chronic stages of neuropathic pain, prefrontal tDCS reversed established allodynia and suppressed aversion and anxiety-related behaviours. Activity mapping as well as in vivo electrophysiological analyses revealed that although the cortex responds to acute tDCS with major excitation, repetitive prefrontal tDCS brings about large-scale silencing of cortical activity. Different classes of different classes of GABAergic interneurons and classes of excitatory neurons differs dramatically between single, acute vs and repetitive tDCS. Repetitive prefrontal tDCS alters basal activity as well as responsivity of a discrete set of distant cortical and sub-cortical areas to tactile stimuli, namely the rostral anterior cingulate cortex, the insular cortex, the ventrolateral periaqueductal grey and the spinal dorsal horn. This study thus makes a strong case for harnessing prefrontal cortical modulation for non-invasive transcranial stimulation paradigms to achieve long-lasting pain relief in established neuropathic pain states and provides valuable insights gained on neural mechanistic underpinnings of prefrontal tDCS in neuropathic pain.
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http://dx.doi.org/10.1016/j.pneurobio.2021.102009DOI Listing
June 2021

Fezf2 expression in layer 5 projection neurons of mature mouse motor cortex.

J Comp Neurol 2016 Mar 30;524(4):829-45. Epub 2015 Aug 30.

Department of Physiology, Brain Health Research Centre, Otago School of Medical Sciences, University of Otago, Dunedin, New Zealand, 9054.

The mature cerebral cortex contains a wide diversity of neuron phenotypes. This diversity is specified during development by neuron-specific expression of key transcription factors, some of which are retained for the life of the animal. One of these key developmental transcription factors that is also retained in the adult is Fezf2, but the neuron types expressing it in the mature cortex are unknown. With a validated Fezf2-Gfp reporter mouse, whole-cell electrophysiology with morphology reconstruction, cluster analysis, in vivo retrograde labeling, and immunohistochemistry, we identify a heterogeneous population of Fezf2(+) neurons in both layer 5A and layer 5B of the mature motor cortex. Functional electrophysiology identified two distinct subtypes of Fezf2(+) neurons that resembled pyramidal tract projection neurons (PT-PNs) and intratelencephalic projection neurons (IT-PNs). Retrograde labeling confirmed the former type to include corticospinal projection neurons (CSpPNs) and corticothalamic projection neurons (CThPNs), whereas the latter type included crossed corticostriatal projection neurons (cCStrPNs) and crossed-corticocortical projection neurons (cCCPNs). The two Fezf2(+) subtypes expressed either CTIP2 or SATB2 to distinguish their physiological identity and confirmed that specific expression combinations of key transcription factors persist in the mature motor cortex. Our findings indicate a wider role for Fezf2 within gene expression networks that underpin the diversity of layer 5 cortical projection neurons.
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http://dx.doi.org/10.1002/cne.23875DOI Listing
March 2016

Phasic Dopamine Modifies Sensory-Driven Output of Striatal Neurons through Synaptic Plasticity.

J Neurosci 2015 Jul;35(27):9946-56

Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, 68159 Mannheim, Germany

Animals are facing a complex sensory world in which only few stimuli are relevant to guide behavior. Value has to be assigned to relevant stimuli such as odors to select them over concurring information. Phasic dopamine is involved in the value assignment to stimuli in the ventral striatum. The underlying cellular mechanisms are incompletely understood. In striatal projection neurons of the ventral striatum in adult mice, we therefore examined the features and dynamics of phasic dopamine-induced synaptic plasticity and how this plasticity may modify the striatal output. Phasic dopamine is predicted to tag inputs that occur in temporal proximity. Indeed, we observed D1 receptor-dependent synaptic potentiation only when odor-like bursts and optogenetically evoked phasic dopamine release were paired within a time window of <1 s. Compatible with predictions of dynamic value assignment, the synaptic potentiation persisted after the phasic dopamine signal had ceased, but gradually reversed when odor-like bursts continued to be presented. The synaptic plasticity depended on the sensory input rate and was input specific. Importantly, synaptic plasticity amplified the firing response to a given olfactory input as the dendritic integration and the firing threshold remained unchanged during synaptic potentiation. Thus, phasic dopamine-induced synaptic plasticity can change information transfer through dynamic increases of the output of striatal projection neurons to specific sensory inputs. This plasticity may provide a neural substrate for dynamic value assignment in the striatum.
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http://dx.doi.org/10.1523/JNEUROSCI.0127-15.2015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6605413PMC
July 2015

Potentiation of NMDA receptor-mediated transmission in striatal cholinergic interneurons.

Front Cell Neurosci 2015 9;9:116. Epub 2015 Apr 9.

Department of Anatomy and the Brain Health Research Centre, University of Otago Dunedin, New Zealand.

Pauses in the tonic firing of striatal cholinergic interneurons (CINs) emerge during reward-related learning in response to conditioning of a neutral cue. We have previously reported that augmenting the postsynaptic response to cortical afferents in CINs is coupled to the emergence of a cell-intrinsic afterhyperpolarization (AHP) underlying pauses in tonic activity. Here we investigated in a bihemispheric rat-brain slice preparation the mechanisms of synaptic plasticity of excitatory afferents to CINs and the association with changes in the AHP. We found that high frequency stimulation (HFS) of commissural corticostriatal afferents from the contralateral hemisphere induced a robust long-term depression (LTD) of postsynaptic potentials (PSP) in CINs. Depression of the PSP of smaller magnitude and duration was observed in response to HFS of the ipsilateral white matter or cerebral cortex. In Mg(2+)-free solution HFS induced NMDA receptor-dependent potentiation of the PSP, evident in both the maximal slope and amplitude of the PSP. The increase in maximal slope corroborates previous findings, and was blocked by antagonism of either D1-like dopamine receptors with SCH23390 or D2-like dopamine receptors with sulpiride during HFS in Mg(2+)-free solution. Potentiation of the slower PSP amplitude component was due to augmentation of the NMDA receptor-mediated potential as this was completely reversed on subsequent application of the NMDA receptor antagonist AP5. HFS similarly potentiated NMDA receptor currents isolated by blockade of AMPA/kainate receptors with CNQX. The plasticity-induced increase in the slow PSP component was directly associated with an increase in the subsequent AHP. Thus plasticity of cortical afferent synapses is ideally suited to influence the cue-induced firing dynamics of CINs, particularly through potentiation of NMDA receptor-mediated synaptic transmission.
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http://dx.doi.org/10.3389/fncel.2015.00116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4391264PMC
April 2015

Phasic dopaminergic activity exerts fast control of cholinergic interneuron firing via sequential NMDA, D2, and D1 receptor activation.

J Neurosci 2014 Aug;34(35):11549-59

Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, 68159 Mannheim, Germany,

Phasic increases in dopamine (DA) are involved in the detection and selection of relevant sensory stimuli. The DAergic and cholinergic system dynamically interact to gate and potentiate sensory inputs to striatum. Striatal cholinergic interneurons (CINs) respond to relevant sensory stimuli with an initial burst, a firing pause, or a late burst, or a combination of these three components. CIN responses coincide with phasic firing of DAergic neurons in vivo. In particular, the late burst of CINs codes for the anticipated reward. To examine whether DAergic midbrain afferents can evoke the different CIN responses, we recorded from adult olfactory tubercle slices in the mouse ventral striatum. Olfactory inputs to striatal projection neurons were gated by the cholinergic tone. Phasic optogenetic activation of DAergic terminals evoked combinations of initial bursts, pauses, and late bursts in subsets of CINs by distinct receptor pathways. Glutamate release from midbrain afferents evoked an NMDAR-dependent initial burst followed by an afterhyperpolarization-induced pause. Phasic release of DA itself evoked acute changes in CIN firing. In particular, in CINs without an initial burst, phasic DA release evoked a pause through D2-type DA receptor activation. Independently, phasic DA activated a slow depolarizing conductance and the late burst through a D1-type DA receptor pathway. In summary, DAergic neurons elicit transient subsecond firing responses in CINs by sequential activation of NMDA, D2-type, and D1-type receptors. This fast control of striatal cholinergic tone by phasic DA provides a novel dynamic link of two transmitter systems central to the detection and selection of relevant stimuli.
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http://dx.doi.org/10.1523/JNEUROSCI.1175-14.2014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6608407PMC
August 2014

Expression of the developmental transcription factor Fezf2 identifies a distinct subpopulation of layer 5 intratelencephalic-projection neurons in mature mouse motor cortex.

J Neurosci 2014 Mar;34(12):4303-8

Departments of Physiology and Biochemistry, Brain Health Research Centre, Otago School of Medical Sciences, University of Otago, Dunedin, New Zealand 9016.

The transcription factor encoded by Fez family zinc finger 2 (Fezf2) is necessary for normal development of the cerebral cortex. However, Fezf2 continues to be expressed in the mature brain, indicating that it might also be necessary for cortical function throughout life. Here, we show a unique identity of Fezf2-expressing intratelencephalic-projection neurons (IT-PNs) in layer 5 of the mature mouse motor cortex, using a Fezf2-Gfp reporter mouse, in vivo retrograde labeling, whole-cell electrophysiology with morphology reconstruction, and cluster analysis. Fezf2-expressing IT-PNs occupy layer 5A and display an apical dendritic tuft; functionally, they fire broad, adapting action potentials and exhibit an Ih-mediated voltage sag that influences their synaptic properties. In contrast, IT-PNs without Fezf2 expression mainly occupy layer 5B, do not display a tuft, and exhibit regular action potential firing and little sag. Both groups of IT-PNs demonstrated distinct frequency-selective synaptic responses to commissural inputs, indicating unique contributions within the cortical microcircuitry. Our findings establish a new, distinct physiological identity of Fezf2-expressing neurons within mature motor cortex.
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http://dx.doi.org/10.1523/JNEUROSCI.3111-13.2014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6608095PMC
March 2014

Diversity of layer 5 projection neurons in the mouse motor cortex.

Front Cell Neurosci 2013 16;7:174. Epub 2013 Oct 16.

Department of Physiology, Brain Health Research Centre, Otago School of Medical Sciences, University of Otago Dunedin, New Zealand.

In the primary motor cortex (M1), layer 5 projection neurons signal directly to distant motor structures to drive movement. Despite their pivotal position and acknowledged diversity these neurons are traditionally separated into broad commissural and corticofugal types, and until now no attempt has been made at resolving the basis for their diversity. We therefore probed the electrophysiological and morphological properties of retrogradely labeled M1 corticospinal (CSp), corticothalamic (CTh), and commissural projecting corticostriatal (CStr) and corticocortical (CC) neurons. An unsupervised cluster analysis established at least four phenotypes with additional differences between lumbar and cervical projecting CSp neurons. Distinguishing parameters included the action potential (AP) waveform, firing behavior, the hyperpolarisation-activated sag potential, sublayer position, and soma and dendrite size. CTh neurons differed from CSp neurons in showing spike frequency acceleration and a greater sag potential. CStr neurons had the lowest AP amplitude and maximum rise rate of all neurons. Temperature influenced spike train behavior in corticofugal neurons. At 26°C CTh neurons fired bursts of APs more often than CSp neurons, but at 36°C both groups fired regular APs. Our findings provide reliable phenotypic fingerprints to identify distinct M1 projection neuron classes as a tool to understand their unique contributions to motor function.
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http://dx.doi.org/10.3389/fncel.2013.00174DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3797544PMC
October 2013

Visual-induced excitation leads to firing pauses in striatal cholinergic interneurons.

J Neurosci 2011 Aug;31(31):11133-43

Department of Anatomy and Structural Biology, Brain Health Research Centre, University of Otago, Dunedin 9054, New Zealand.

Tonically active neurons in the primate striatum, believed to be cholinergic interneurons (CINs), respond to sensory stimuli with a pronounced pause in firing. Although inhibitory and neuromodulatory mechanisms have been implicated, it is not known how sensory stimuli induce firing pauses in CINs in vivo. Here, we used intracellular recordings in anesthetized rats to investigate the effectiveness of a visual stimulus at modulating spike activity in CINs. Initially, no neuron was visually responsive. However, following pharmacological activation of tecto-thalamic pathways, the firing pattern of most CINs was significantly modulated by a light flashed into the contralateral eye. Typically, this induced an excitation followed by a pause in spike firing, via an underlying depolarization-hyperpolarization membrane sequence. Stimulation of thalamic afferents in vitro evoked similar responses that were independent of synaptic inhibition. Thus, visual stimulation likely induces an initial depolarization via a subcortical tecto-thalamo-striatal pathway, pausing CIN firing through an intrinsic afterhyperpolarization.
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http://dx.doi.org/10.1523/JNEUROSCI.0661-11.2011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6623370PMC
August 2011

Enhanced high-frequency membrane potential fluctuations control spike output in striatal fast-spiking interneurones in vivo.

J Physiol 2011 Sep 11;589(17):4365-81. Epub 2011 Jul 11.

J. M. Schulz: Department of Physiology, University of Bern, Bühlplatz 5, 3012 Bern, Switzerland.

Fast-spiking interneurones (FSIs) constitute a prominent part of the inhibitory microcircuitry of the striatum; however, little is known about their recruitment by synaptic inputs in vivo. Here, we report that, in contrast to cholinergic interneurones (CINs), FSIs (n = 9) recorded in urethane-anaesthetized rats exhibit Down-to-Up state transitions very similar to spiny projection neurones (SPNs). Compared to SPNs, the FSI Up state membrane potential was noisier and power spectra exhibited significantly larger power at frequencies in the gamma range (55-95 Hz). The membrane potential exhibited short and steep trajectories preceding spontaneous spike discharge, suggesting that fast input components controlled spike output in FSIs. Spontaneous spike data contained a high proportion (43.6 ± 32.8%) of small inter-spike intervals (ISIs) of <30 ms, setting FSIs clearly apart from SPNs and CINs. Cortical-evoked inputs had slower dynamics in SPNs than FSIs, and repetitive stimulation entrained SPN spike output only if the stimulation was delivered at an intermediate frequency (20 Hz), but not at a high frequency (100 Hz). Pharmacological induction of an activated ECoG state, known to promote rapid FSI spiking, mildly increased the power (by 43 ± 55%, n = 13) at gamma frequencies in the membrane potential of SPNs, but resulted in few small ISIs (<30 ms; 4.3 ± 6.4%, n = 8). The gamma frequency content did not change in CINs (n = 8). These results indicate that FSIs are uniquely responsive to high-frequency input sequences. By controlling the spike output of SPNs, FSIs could serve gating of top-down signals and long-range synchronisation of gamma-oscillations during behaviour.
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http://dx.doi.org/10.1113/jphysiol.2011.212944DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3180588PMC
September 2011

IH current generates the afterhyperpolarisation following activation of subthreshold cortical synaptic inputs to striatal cholinergic interneurons.

J Physiol 2009 Dec;587(Pt 24):5879-97

Department of Anatomy and Structural Biology, Otago School of Medical Sciences, University of Otago, PO Box 913, Dunedin, New Zealand.

Pauses in the tonic firing of striatal cholinergic interneurons emerge during reward-related learning and are triggered by neutral cues which develop behavioural significance. In a previous in vivo study we have proposed that these pauses in firing may be due to intrinsically generated afterhyperpolarisations (AHPs) evoked by excitatory synaptic inputs, including those below the threshold for action potential firing. The aim of this study was to investigate the mechanism of the AHPs using a brain slice preparation which preserved both cerebral hemispheres. Augmenting cortically evoked postsynaptic potentials (PSPs) by repetitive stimulation of cortical afferents evoked AHPs that were unaffected by blocking either GABA(A) receptors with bicuculline, or GABA(B) receptors with saclofen or CGP55845. Apamin (a blocker of small conductance Ca(2+)-activated K(+) channels) had minimal effects, while chelation of intracellular Ca(2+) with BAPTA reduced the AHP by about 30%. In contrast, blocking hyperpolarisation and cyclic nucleotide activated (HCN) cation current (I(H)) with ZD7288 or Cs(+) diminished the size of the AHPs by 60% and reduced the proportion of episodes that contained this hyperpolarisation. The reversal potential (20 mV) and voltage dependence of the AHPs were consistent with the hypothesis that a transient deactivation of I(H) caused most of the AHP at hyperpolarised potentials, while the slow AHP-type Ca(2+)-activated K(+) channels increasingly contributed at more depolarised membrane potentials. Subthreshold somatic current injections yielded similar AHPs with a median duration of approximately 700 ms that were not affected by firing of a single action potential. These results indicate that transient deactivation of HCN channels evokes pauses in tonic firing of cholinergic interneurons, an event likely to be elicited by augmentation of afferent synaptic inputs during learning.
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http://dx.doi.org/10.1113/jphysiol.2009.177600DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2808546PMC
December 2009

Location and connectivity determine GABAergic interneuron survival in the brains of South Hampshire sheep with CLN6 neuronal ceroid lipofuscinosis.

Neurobiol Dis 2008 Oct 25;32(1):50-65. Epub 2008 Jun 25.

Agriculture and Life Sciences Division, Lincoln University, Lincoln 7647, New Zealand.

The neuronal ceroid lipofuscinoses (NCLs, Batten disease) are fatal inherited neurodegenerative diseases. Sheep affected with the CLN6 form provide a valuable model to investigate underlying disease mechanisms from preclinical stages. Excitatory neuron loss in these sheep is markedly regional, localized early reactive changes accurately predicting neuron loss and subsequent symptom development. This investigation of GABAergic interneuron loss revealed similar regional effects that correlate with symptoms. Loss of parvalbumin positive neurons from the affected cortex was apparent at four months and became profound by 19 months, as was somatostatin positive neuron loss to a lesser extent. Conversely calbindin and neuropeptide Y positive neurons were relatively preserved and calretinin staining temporarily increased. Staining of subcortical regions was more intense but subcortical architecture remained relatively intact. Discrete subcortical changes followed from cortical changes in interconnected regions. These data highlight cellular location and interconnectivity as the major determinants of neuron survival, rather than phenotype.
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http://dx.doi.org/10.1016/j.nbd.2008.06.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2647510PMC
October 2008

The development and characterisation of complex ovine neuron cultures from fresh and frozen foetal neurons.

J Neurosci Methods 2006 Jul 17;155(1):98-108. Epub 2006 Feb 17.

Agriculture and Life Sciences Division, Lincoln University, Canterbury, New Zealand.

Cultures of ovine cerebral and cerebellar neurons from mid-term sheep foetal brains, 9-15 weeks old, have been established for the first time. These foetal brains are relatively mature, being at similar stages of development as peri and post-natal rodent brains. Cultures were routinely maintained for 3-4 weeks, and longer. Nearly all the cells from the younger foetuses adhered as neurons. The proportion of glial cells increased with age, as did the risk of cultures being overtaken by glial cells. Cultured neurons were bipolar, tripolar and multipolar, similar to the morphologies of neurons in vivo. Older foetuses also yield more complex neurons, notably giant cells. Other properties of the cultured neurons also mimic in vivo observations, including neurite beading, complexity in neurotransmitter class (GABAergic and glutamatergic) and calcium binding protein (calbindin and calretinin) content. Single cell divisions of neurons were observed in younger cultures by time-lapse photography and the occurrence of telophase nuclei. The advantage of the high yield of genetically identical cells obtained from a single sheep foetus, 150 million, was extended by cryopreservation of neurons after snap freezing, and later culture. These cultures showed the same characteristics as cultures from the freshly plated cells.
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http://dx.doi.org/10.1016/j.jneumeth.2006.01.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1525139PMC
July 2006

Glial activation spreads from specific cerebral foci and precedes neurodegeneration in presymptomatic ovine neuronal ceroid lipofuscinosis (CLN6).

Neurobiol Dis 2005 Oct;20(1):49-63

Agriculture and Life Sciences Division, Lincoln University, PO Box 84, Canterbury, New Zealand.

The neuronal ceroid lipofuscinoses (NCLs, Batten disease) are fatal inherited neurodegenerative diseases characterized by gross brain atrophy, blindness, and intracellular accumulation of lysosome-derived storage bodies. A CLN6 form in sheep is studied as a large animal model of the human diseases. This study describes neuropathological changes in brains from presymptomatic affected sheep. Activated astrocytes and focal clusters of activated microglia were present in outer layers of occipital and somatosensory cortical regions as early as 12 days of age, together with activated perivascular macrophages. Astrocytic activation and progressive transformation of microglia to brain macrophages preceded neurodegeneration and spread to different cortical areas, most prominently in regions associated with clinical symptoms. In contrast, storage body accumulation was much more evenly spread across regions. These data support suggestions that neurodegeneration and storage body accumulation may be independent manifestations of CLN6 mutation and indicate that glial cell activation may be an important mediator in pathogenesis.
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http://dx.doi.org/10.1016/j.nbd.2005.01.025DOI Listing
October 2005

The origin of fluorescence in the neuronal ceroid lipofuscinoses (Batten disease) and neuron cultures from affected sheep for studies of neurodegeneration.

Arch Gerontol Geriatr 2002 May-Jun;34(3):343-57

Animal and Food Sciences Division, Lincoln University, Canterbury, New Zealand.

Lipofuscin and ceroid are usually held responsible for impaired cellular performance, via oxidative damage and the irreversible accumulation of fluorescent products of lipid peroxidation. The neuronal ceroid lipofuscinoses (NCLs, Batten disease) are inherited neurodegenerative diseases characterized by intracellular accumulation of fluorescent lipofuscin-like bodies. However these bodies are lysosomes packed with a particular protein, subunit c of mitochondrial ATP synthase; not the result of oxidative damage. No individual storage body component was fluorescent nor were solutions of total storage bodies. UV-vis spectra confirmed the lack of a fluorophor. Crystals of non-fluorescent albumin and reconstituted storage bodies were fluorescent in glycerol suspensions. This fluorescence is probably caused by interference of light reflected from the protein array, as is often observed in protein crystals. Other lipofuscins may be secondary lysosomes with a high protein content and the source of fluorescence the same. The neurodegeneration associated with lipofuscin accumulation may be caused by that accumulation, or may be a separate manifestation of aging. Neuronal cell cultures offer a way to study these processes. Subunit c accumulation has been observed in cerebral bipolar neurons cultured from 90 day NCL affected sheep foetuses. Neurons from different parts of the brain behave differently. Normal 108 day cerebellar granule neurons migrated into clumps when cultured with tri-iodothyronine, but affected cerebellar neurons did not, nor did normal or affected cerebral neurons.
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http://dx.doi.org/10.1016/s0167-4943(02)00011-0DOI Listing
March 2004
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