Cerebellar Purkinje cell stripe patterns reveal a differential vulnerability and resistance to cell loss during normal aging in mice

Aging involves the gradual loss of brain cells and a decline in physical and cognitive capabilities. One brain region affected by aging is the cerebellum, which is best known for its role in motor coordination.

During healthy aging, the cerebellum is reduced in size, and elderly individuals often face difficulties with balance and motor skills. This shrinkage is partly caused by the loss of neurons, particularly Purkinje cells. A reduction in Purkinje cells and impaired motor function have also been seen in rodents during normal aging.

Furthermore, in many rodent models of disease, not all Purkinje cells are equally likely to die. The surviving cells form specific patterns similar to those seen during cerebellar development. However, it has so far been unclear whether such regional differences in Purkinje cell loss also occur during healthy aging. Addressing this question would shed light on how aging influences cellular susceptibility and resilience in the cerebellum and how these cellular responses affect motor function and age-related cell death.

To find out whether loss of Purkinje cells in aged mice occurs in a similar pattern observed during disease, Donofrio et al. used a combination of genetic, histological, and imaging techniques to visualize Purkinje cells in the cerebellum.

The results revealed that the loss of Purkinje cells in healthy aged mice occurred in a pattern similar to that often observed in models of disease. However, the overall pattern in aged mice was distinct and occurred in a parasagittal, striped pattern – that is, long, narrow, and running front-to-back through the cerebellum. In addition, examining human cerebellum tissue samples collected from individuals without any reported neurological or neuropsychiatric problems confirmed a loss of Purkinje cells that increased with age. However, a specific pattern remains to be confirmed.

Our study reveals a cerebellar framework of vulnerability and resistance to age-related cell death. These findings could enhance healthy brain aging by improving the precision of targeted therapeutics and opening avenues for preventative strategies to reduce or prevent cell loss. The essential step is to fully understand when and how cerebellar neurons degenerate across the human lifespan.

In addition to its well-known roles in motor function, the cerebellum is also involved in cognitive functions that include executive function, visuospatial memory, language, and emotional processing (Stoodley et al., 2012; Strick et al., 2009; Reeber et al., 2013; Rudolph et al., 2023; Timmann and Daum, 2007; Berlijn et al., 2024; Schmahmann, 2019; Kim et al., 2024; Clausi et al., 2022; Adamaszek et al., 2017; Van Overwalle et al., 2020). Accordingly, the cerebellum is a major culprit in movement disorders (Marsden, 2018; Klockgether et al., 2019; Holmes, 1917; Holmes, 1939; Marin-Lahoz and Gironell, 2016; Louis, 2016; Benito-León and Labiano-Fontcuberta, 2016; Handforth, 2016; Filip et al., 2016; Cerasa and Quattrone, 2016; Shakkottai et al., 2017; Louis and Faust, 2020; Mukherjee and Pandey, 2024; Merola et al., 2019; Kumar et al., 2023; van der Heijden and Sillitoe, 2023), and it likely also contributes to autism spectrum disorders (Sydnor and Aldinger, 2022; Kelly et al., 2021; Su et al., 2021; Hampson and Blatt, 2015; D’Mello and Stoodley, 2015; Rogers et al., 2013; Fatemi et al., 2012), sleep disturbances (Jackson and Xu, 2023; Torres-Herraez et al., 2022; Xu et al., 2021; Salazar Leon et al., 2024; Salazar Leon and Sillitoe, 2022), and schizophrenia (Faris et al., 2024; Khalil et al., 2022; Cao and Cannon, 2019). Despite the prevalence of cerebellar involvement in disease, the cerebellum is often overlooked in the context of aging. This omission has not gone unnoticed, with recent arguments for incorporating the cerebellum into our understanding of brain aging, which has historically focused on the cerebral cortex and hippocampus (Bernard, 2022). In support of this hypothesis, motor and cognitive behaviors are often impaired during normal aging. The decline in these behaviors could, in theory, be accompanied by cerebellar pathology, such as variations in cerebellar volume and alterations in its circuit connectivity (Bernard and Seidler, 2014; Arleo et al., 2024; Iskusnykh et al., 2024). Therefore, the cerebellum is a potentially critical model system for better understanding the structure and function of the brain during aging.

Although neurodegeneration is associated with disease pathogenesis, cerebellar degeneration can also occur during aging in the absence of disease. Elderly patients have decreased cerebellar volume compared to young patients (Raz et al., 1998; Raz et al., 2001; Raz et al., 2013; Jernigan et al., 2001), and longitudinal studies have shown decreased cerebellar volume in healthy older individuals over time (Tang et al., 2001; Raz et al., 2005; Smith et al., 2007; Raz et al., 2010; Han et al., 2020). At the cellular level, otherwise healthy aged patients have significantly decreased Purkinje cell density (Andersen et al., 2003; Torvik et al., 1986; Sjobeck et al., 1999). Depending on severity, age-related cerebellar atrophy can have detrimental and often debilitating effects on motor function. For example, decreased cerebellar volume in the elderly is correlated with impaired eyeblink conditioning, a cerebellum-dependent associative learning task, as well as slower gait and impaired balance, two aspects of motor function that involve the cerebellum (Woodruff Pak et al., 2001, Rosano et al., 2007). Furthermore, there are reported structure-function relationships between the volume of specific cerebellar regions and the performance of sensorimotor tasks in young and old participants (Bernard and Seidler, 2013). These results suggest that cerebellar atrophy is associated with deficits in cerebellum-related functions during normal aging. However, the cellular nature of this structure-function relationship is still poorly understood.

Similar to humans, control mice and rats also experience Purkinje cell loss during aging (Bakalian et al., 1991; Hadj-Sahraoui et al., 1996; Hadj-Sahraoui et al., 1997; Doulazmi et al., 1999; Doulazmi et al., 2006; Sturrock, 1989a; Sturrock, 1989b; Sturrock, 1990; Zanjani et al., 2004; Childs et al., 2021), as well as motor dysfunction. At around 12 months of age, mice begin to display impaired performance on the rotarod task, a test of motor coordination and motor learning (Caston et al., 1995; Vogel et al., 2002; Shoji and Miyakawa, 2019), as well as impaired eyeblink conditioning (Vogel et al., 2002), now a classical test for Pavlovian learning. Interestingly, there is evidence to suggest that mice have significantly decreased Purkinje cell numbers starting at 18 months, corresponding with impaired delay eyeblink conditioning (Woodruff Pak, 2006). These studies suggest that cerebellum-associated motor function declines with age in mice and that this decline may be accompanied by Purkinje cell loss. However, the precise regionality of the cerebellum was not considered in these studies, and we argue that age-related changes follow a fundamental scheme.

Compared to the patterned Purkinje cell loss reported in different disease models, relatively little is known about how Purkinje cell loss affects different regions of the cerebellum during normal aging. Neuroimaging in humans has revealed that cerebellar volume in different lobules can be differentially affected by aging (Raz et al., 1998; Han et al., 2020; Bernard and Seidler, 2013; Luft et al., 1999; Hulst et al., 2015; Yu et al., 2017; Wang et al., 2024). However, a closer examination of any region-specific cellular differences is lacking. Other studies have found minimal regional differences beyond the observation that most age-related Purkinje cell loss seems to occur in the anterior cerebellum (Andersen et al., 2003, Torvik et al., 1986). In fact, multiple studies have found that Purkinje cell loss is uniform across the latero-lateral extent of the cerebellar cortex in rodents (Bakalian et al., 1991; Hadj-Sahraoui et al., 1996; Hadj-Sahraoui et al., 1997; Doulazmi et al., 1999; Doulazmi et al., 2006; Sturrock, 1990). However, cerebellar organization and patterning are much more complex than the broad medio-lateral and anterior-posterior differences can account for.

The cerebellum is highly compartmentalized on multiple levels as determined by genetics and developmental, anatomical, and electrophysiological studies. Based on development and gene expression boundaries, the cerebellum can be divided into transverse zones: the anterior (lobules I-V), central (lobules VI and VII), posterior (lobule VIII and anterior lobule IX), and nodular (posterior lobule IX and lobule X) zones (Ozol et al., 1999). Within each transverse zone, subpopulations of Purkinje cells are divided into stripes based on gene expression patterns, which differ between transverse zones (Marzban et al., 2004; Sarna et al., 2006; Chung et al., 2008; Demilly et al., 2011; Brochu et al., 1990; Armstrong et al., 2000; Dehnes et al., 1998). Numerous stripe markers exist, with overlapping, partially overlapping, or unique expression patterns. The most well-studied stripe marker is zebrin II (Hawkes and Herrup, 1995; Ebner et al., 2012; Gravel et al., 1987), the expression pattern of which is remarkably consistent from animal to animal and conserved across mammals (Sillitoe et al., 2005; Sillitoe and Joyner, 2007). The identity of individual Purkinje cells, which can express different combinations of patterned markers, is established when each Purkinje cell is born (Hashimoto and Mikoshiba, 2003; Namba et al., 2011; Dastjerdi et al., 2012; Tran-Anh et al., 2020), although the exact relationship between developmental Purkinje cell clusters and adult stripes has been only partially resolved (Larouche and Hawkes, 2006). The cerebellar stripe patterns represent one component of a greater network architecture. For example, longitudinal groups of Purkinje cells are related in the rostrocaudal axis based on specific inputs from the inferior olive through climbing fibers and specific outputs to the cerebellar nuclei through the Purkinje cell axons (Apps and Hawkes, 2009). Each longitudinal zone, together with its efferent and afferent pathways, comprises a functional unit referred to as a cerebellar module (Ruigrok, 2011). Based on these overlapping levels of organization, the cerebellum is predicted to be composed of hundreds or thousands of modules. This hypothesis posits that the multiple maps of cerebellar compartmentation that are visualized with different approaches comprise a single overarching map, with alignment between zones, stripes, and modules (Apps and Hawkes, 2009). Here, we wondered whether the patterns that are revealed by stripe markers reflect a map of Purkinje cell degeneration and eventual cell loss with age and if there is a functional significance to this patterned cellular demise.

To test for and investigate the potential contribution of patterned Purkinje cell loss to aging in mice, we used a combination of whole-mount immunohistochemistry (Sillitoe and Hawkes, 2002; White et al., 2012) and analysis of Purkinje cell patterns on histological tissue slices. These techniques enabled us to visualize Purkinje cells across the surfaces of entire cerebella of normal aged mice and examine their cellular level changes, respectively. We also used genetically driven fluorescent reporter labeling to specifically label Purkinje cells. Using these techniques, we uncovered that some, but not all, aged mice have Purkinje cell loss that occurs in a pattern of parasagittal stripes. In addition, upon immunostaining coronal sections of cerebellar tissue, we found that the pattern of age-related Purkinje cell loss is unique compared to the most common patterns of Purkinje cell loss that have been reported in numerous mouse models of disease. Behavioral tests revealed deficits in motor function in aged mice compared to young mice. Finally, we observed patches of Purkinje cell degeneration in postmortem tissue obtained from neurologically normal humans. We therefore have three key findings to report in this series of studies: (1) Purkinje cell degeneration and cell loss are prominent features of the otherwise healthy aging mouse cerebellum, (2) Purkinje cell loss during normal aging in mice does not occur in a random manner and instead occurs in an array of parasagittal stripes that reflect the normal developmental, anatomical, and functional topography of the mammalian cerebellum, and (3) this mode of patterned cell loss may be conserved and reflect a fundamental heterogeneity of the human cerebellum that distinguishes cells that are vulnerable versus resistant to deterioration in health and disease. Together, these data underscore the potential clinical significance of our findings of patterned Purkinje cell degeneration and loss in normal aging mice, as they may inform the design and development of effective therapies for specific neurological and neuropsychiatric conditions that are defined by compromised cerebellar structure and function.

Adult-onset neurodegeneration typically impacts specific regions of the brain. For instance, in diseases such as Alzheimer’s disease and Parkinson’s disease, neurodegeneration affects the cortex and basal ganglia, resulting in defective cognitive versus motor circuits, respectively. A similar phenomenon occurs during normal aging, as certain brain regions are more susceptible to degeneration (Pandya and Patani, 2021). Interestingly, the cerebellum is a target in age-related degeneration, and its cellular demise can lead to both cognitive and motor impairments. We examine whether different populations of cells are more susceptible than others. What dictates this regional vulnerability and whether these processes and sensitive neuronal subpopulations are the same across different diseases and typical aging is unknown. To begin to address this problem, here we sought to test whether cerebellar Purkinje cell loss follows a region-specific pattern during normal aging.

Aged mice have Purkinje cell loss that occurs in parasagittal stripes

We started by asking whether normal mice exhibit patterned Purkinje cell loss during aging. Previous studies have relied on tissue sections alone for identifying the presence of degeneration and cell loss, although studying the complexity of the cerebellum on individual slices limits one’s ability to visualize topographic patterns. In our study, to test whether age-related Purkinje cell loss is indeed patterned, we examined a total of 52 cerebella from aged mice (between 13 and 25 months of age; Table 1). We used a combination of techniques to visualize Purkinje cells, including whole-mount immunohistochemistry (Sillitoe and Hawkes, 2002; White et al., 2012) with calbindin antibodies (n=5), whole-mount and light sheet imaging of a Purkinje-cell-specific reporter in transgenic mice (n=21 and n=2, respectively), and histology on coronal tissue sections (n=34; Table 1). Using these techniques, we observed that Purkinje cell loss across the cerebella of aged mice is not uniform, as has been previously reported (Bakalian et al., 1991; Hadj-Sahraoui et al., 1996; Hadj-Sahraoui et al., 1997; Doulazmi et al., 1999; Doulazmi et al., 2006; Sturrock, 1990), but forms a pattern. Importantly, the pattern is composed of parasagittal stripes that are symmetrical about the midline. In the calbindin-labeled whole-mount cerebella, the stripes appear as alternating dark stripes of surviving Purkinje cells and light stripes where Purkinje cells have presumably degenerated (Figure 1A). The stripes are visible in the anterior, central, and posterior zones of the cerebellum, as well as in the paraflocculi. Closer inspection of the whole-mount cerebella revealed the shapes of individual Purkinje cells within the dark stripes, with the dendrites and cell bodies clearly visible (Figure 1B). Purkinje cell axons with torpedoes, a pathological sign of Purkinje cell neurodegeneration in disease (Louis et al., 2009) and normal aging (Bäurle and Grüsser-Cornehls, 1994), were also observed in whole-mount cerebella (Figure 1B). The presence of the axonal pathology suggests that the observed Purkinje cell loss in aged mice may be due to and potentially accompanied by a process of neurodegeneration that causes cell loss over time.

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Table 1

Sex	Age (months)	PC loss	Genotype	Littermates	Technique
M	7	striped PC loss	Pcp2Cre+/-;ROSA26Ai40D	a	GFP whole-mount
F	7.2	no PC loss	Pcp2Cre+/-;ROSA26Ai40D		GFP whole-mount
M	7.4	no PC loss	no mutant alleles	a	coronal sections
F	11.7	striped PC loss	Pcp2Cre+/-;ROSA26Ai40D	b	GFP whole-mount
M	13.7	no PC loss	ROSA26Ai32+/+		coronal sections
M	13.9	striped PC loss	no mutant alleles	c	coronal sections
M	14.3	non-striped PC loss	Pcp2Cre+/-;ROSA26Ai32		GFP whole-mount
M	14.3	striped PC loss	Pcp2Cre+/-;ROSA26Ai32+/+	d	GFP whole-mount
M	14.4	no PC loss	Pcp2Cre+/-;ROSA26Ai3 +/+	d	GFP whole-mount
F	14.5	striped PC loss	Pcp2Cre+/-;ROSA26Ai32+/-		GFP whole-mount
M	14.7	striped PC loss	Taulsl-mGFP-lacZ		calbindin whole-mount
F	15.1	striped PC loss	Pcp2Cre+/-;ROSA26Ai32		GFP whole-mount
M	15.3	striped PC loss	Pcp2Cre+/-;Taulsl-mGFP-lacZ	e	calbindin whole-mount
F	15.3	no PC loss	Taulsl-mGFP-lacZ;ROSA2lsl-DTR+/-	e	calbindin whole-mount
M	15.7	non-striped PC loss	Pdx1Cre+/-		coronal sections
F	16.3	striped PC loss	Taulsl-mGFP-lacZ;ROSA26lsl-DTR+/-		calbindin whole-mount
F	16.4	no PC loss	Taulsl-mGFP-lacZ		coronal sections
F	16.4	striped PC loss	Pcp2Cre+/-;ROSA26Ai40D+/-	f	GFP whole-mount, coronal sections
M	16.5	non-striped PC loss	ROSA26Ai32+/-	g	coronal sections
M	16.5	no PC loss	GdnfCreER+/-;ROSA26Ai32+/-	g	coronal sections
M	16.5	non-striped PC loss	ROSA26Ai32+/-	g	coronal sections
M	16.6	no PC loss	Taulsl-mGFP-lacZ;ROSA26lsl-DTR+/-		coronal sections
F	16.8	striped PC loss	Pcp2Cre+/-;ROSA26Ai40D		GFP whole-mount, coronal sections
M	16.8	no PC loss	no mutant alleles	h	coronal sections
M	16.8	no PC loss	no mutant alleles	h	coronal sections
M	16.9	no PC loss	Pcp2Cre+/-	i	coronal sections
M	16.9	no PC loss	Taulsl-mGFP-lacZ;ROSA26lsl-DTR+/-	i	coronal sections
M	16.9	no PC loss	no mutant alleles	j	coronal sections
M	16.9	no PC loss	no mutant alleles	j	coronal sections
M	17	striped PC loss	Pcp2Cre+/-;ROSA26Ai40D+/-	k	GFP whole-mount, light sheet
M	17.2	striped PC loss	ROSA26lsl-DTR+/-	c	coronal sections
M	17.3	no PC loss	ROSA26Ai40D+/-	k	GFP whole-mount, coronal sections
M	17.4	striped PC loss	Pcp2Cre+/-;ROSA26Ai40D+/-	k	GFP whole-mount
M	17.4	no PC loss	Ai32+/+;VGAT+/fx		coronal sections
F	18	striped PC loss	Pcp2Cre+/-;ROSA26Ai32	b	GFP whole-mount
M	18.3	no PC loss	Mash1CreER+/-;Taulsl-mGFP-lacZ;VGATfx/fx		coronal sections
F	18.3	striped PC loss	Pcp2Cre+/-;ROSA26Ai40D+/-	l	GFP whole-mount
F	18.5	striped PC loss	Pcp2Cre+/-;ROSA26Ai32	m	coronal sections
F	18.9	no PC loss	ROSA26Ai40D+/-	l	coronal sections
F	19.8	non-striped PC loss	Taulsl-mGFP-lacZ;VGATfx/fx		coronal sections
F	20.1	non-striped PC loss	Taulsl-mGFP-lacZ;VGATfx/fx	n	coronal sections
F	20.1	non-striped PC loss	Taulsl-mGFP-lacZ;VGATfx/fx	n	coronal sections
F	20.9	striped PC loss	Pcp2Cre+/-;ROSA26Ai32	m	coronal sections
F	20.9	striped PC loss	Pcp2Cre+/-;ROSA26Ai32	m	coronal sections
M	20.9	striped PC loss	Pcp2Cre+/-;ROSA26Ai32	m	coronal sections
M	21.2	striped PC loss	Pcp2Cre+/-;ROSA26Ai32	b	GFP whole-mount, coronal sections
M	21.2	striped PC loss	Pcp2Cre+/-;ROSA26Ai32	b	GFP whole-mount, coronal sections
M	21.4	striped PC loss	Pcp2Cre+/-;ROSA26Ai40D	o	GFP whole-mount, coronal sections
M	21.4	striped PC loss	Pcp2Cre+/-;ROSA26Ai40D	o	GFP whole-mount, light sheet
F	23.3	no PC loss	VGATfx/fx		calbindin whole-mount
F	25.5	striped PC loss	Pcp2Cre+/-;ROSA26Ai40D+/-	f	GFP whole-mount, coronal sections
M	25.5	striped PC loss	Pcp2Cre+/-;ROSA26Ai40D	f	GFP whole-mount, coronal sections

We observed considerable variability in terms of Purkinje cell loss in the aged mice. Some aged mice displayed a lack of Purkinje cell loss comparable to young control mice, even at 23 months of age (Figure 1D–F). Of the 52 aged cerebella examined, 19 lacked appreciable Purkinje cell loss, 26 had clearly striped Purkinje cell loss, and 7 had Purkinje cell loss that did not appear striped (Table 1; Figure 1—figure supplement 1A). This inconsistency in the loss of Purkinje cells is not due solely to relative age, as a 14-month-old cerebellum had striped Purkinje cell loss (Figure 1G), whereas a 23-month-old cerebellum did not (Figure 1F; Table 1). Despite this, when striped Purkinje cell loss did occur in the aged mice, the neurodegeneration appears progressive, meaning that older mice were more likely to display more widespread Purkinje cell loss compared to younger mice (Figure 1G–I). Aged mice with striped Purkinje cell loss consistently displayed the same pattern of neurodegeneration (Figure 1G–I). Therefore, Purkinje cells that are more susceptible to age-related neurodegeneration may belong to the same subpopulation of neurons and have the same identity across different mice.

Of the 52 aged mice whose cerebella were examined, 32 were male and 20 were female. We found that 12 of the 20 aged female mice and 14 of the 32 aged male mice had striped Purkinje cell loss (Table 1; Figure 1—figure supplement 1A). Analysis of the data with Fisher’s exact test revealed that the presence of striped Purkinje cell loss is not sex dependent. However, a greater percentage of the aged females displayed Purkinje cell loss compared to the aged males (Figure 1—figure supplement 1A), suggesting that females may be more susceptible to Purkinje cell loss during aging. Overall, these results suggest that there is considerable variability plus context specificity in the spatiotemporal features of Purkinje cell degeneration, eventual Purkinje cell loss, and their associated pattern among aged mice.

Interestingly, among mice born in the same litter, we found that one littermate could have striped Purkinje cell loss while the other littermate did not (Figure 1E and H). This observation was especially evident as observed on surface mapping using the whole-mount immunohistochemical staining approach (Figure 1). This difference in cell loss was observed in five sets of littermates, with each set from a different litter (Table 1). These data suggest that even genetically similar mice raised in the same cage can display dramatic differences in age-related neurodegeneration.

Taken together, these findings suggest that (1) Purkinje cell subpopulations are differentially vulnerable to death during normal aging; (2) the loss of Purkinje cells, according to age-related vulnerability, can result specifically in a striking pattern of parasagittal stripes; and (3) the presence or absence of striped Purkinje cell loss in aged mice is not driven solely by sex or relative age.

Age-related Purkinje cell loss is due to neurodegeneration and the loss of cells

In mouse models with neurodegenerative ataxia, calbindin and other Purkinje-cell-specific genes and proteins are downregulated prior to the onset of motor dysfunction and Purkinje cell loss (Vig et al., 1998; Hansen et al., 2013). This molecular signature raises the possibility that the indication of Purkinje cell loss revealed by antibody staining may in fact be the result of reduced Purkinje cell marker expression rather than neurodegeneration. To distinguish between these possibilities, we tested whether Purkinje cells in aged mice were degenerating. First, we observed common hallmarks of Purkinje cell neurodegeneration, such as thickened axons, axonal torpedoes, and shrunken dendritic arbors, in aged mice with striped Purkinje cell loss (n=8) but not in young mice (n=5; Figure 2A and B). Quantification of molecular layer thickness in lobule VIII revealed that aged mice with striped Purkinje cell loss have significantly thinner molecular layers compared to young mice (Figure 2C), likely due to the regressed dendrites of degenerating Purkinje cells. Aged mice without Purkinje cell loss have minimal axonal pathology (Figure 2A), and the thickness of the molecular layer is comparable to that of young mice (Figure 2B and C), suggesting that in aged mice without Purkinje cell loss, Purkinje cells are not undergoing major neurodegeneration. We also confirmed whether the pattern of Purkinje cell loss was the same using two different calbindin antibodies (young n=4, aged n=6; Figure 2—figure supplement 1).

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Second, to verify that the loss of Purkinje cells was not due to downregulation of calbindin specifically, we used Neutral Red, a dye that stains lysosomes, to label surviving cells in cerebellar tissue (Brandenburg and Blatt, 2022). Adjacent tissue sections were immunostained for calbindin and/or stained with Neutral Red to locate regions with striped Purkinje cell loss. In the aged mice (n=6), regions of the Purkinje cell and molecular layers without calbindin staining, which indicated missing Purkinje cells, also lacked Neutral Red-positive cell bodies, which based on their morphology were easily distinguished from other cell types by their size and position in young mice (n=6; Figure 2D).

Third, to verify the presence of striped Purkinje cell degeneration during normal aging, we used adult Purkinje-cell-specific fluorescent reporter mice, which express a fluorescent reporter specifically in all Purkinje cells because the reporter is driven by Pcp2^Cre. These mice present two advantages for visualizing age-related Purkinje cell loss: (1) Cre expression begins on E17 and continues until all Purkinje cells express Cre in adulthood (Lewis et al., 2004), meaning that even if Pcp2 gene and protein expression are downregulated in advanced age (Cooper et al., 2024) or prior to neurodegeneration (Hansen et al., 2013), reporter expression will remain constant, as it would have already been activated in all Purkinje cells, and its perdurance would allow continued marking of the recombined cells; and (2) Purkinje-cell-specific reporter expression allows for the visualization of Purkinje cells without relying on calbindin, which can be downregulated with advanced age (Cooper et al., 2024; Iacopino and Christakos, 1990; Iacopino et al., 1990) or prior to neurodegeneration (Vig et al., 1998; Hansen et al., 2013). We found that the cerebella of young Purkinje-cell-specific fluorescent reporter mice (n=4) displayed uniform reporter expression across the surface, whereas the cerebella of aged Purkinje-cell-specific fluorescent reporter mice (n=17) displayed reporter expression in alternating parasagittal stripes of greater and lesser intensity (Figure 3A and B). Furthermore, middle-aged mice (11–15 months old; n=4) tended to have less pronounced bands compared to mice 16 months and older, which had clearer, more widespread bands (Figure 3A and B), suggesting a progression of Purkinje cell loss with advanced age. The cerebella of middle-aged mice have striped reporter expression in the anterior zone, large regions with reduced reporter expression in the medial vermis and paravermis, and alternating bands in lobule VIII (Figure 3A and B), suggesting that age-related Purkinje cell loss may begin in these regions before spreading with advancing age. To confirm that the Purkinje-cell-specific reporter expression and the calbindin whole-mount staining reflected the same pattern, we co-stained coronal cerebellar tissue sections of Purkinje-cell-specific fluorescent reporter mice for calbindin and GFP. In young mice, both calbindin and GFP were expressed in all Purkinje cells (n=3), and in aged mice, calbindin and GFP were expressed in identical, overlapping stripes (n=5; Figure 3D, Figure 3—figure supplement 1) that reflected the pattern of age-related Purkinje cell loss. These data indicate that the pattern of age-related Purkinje cell loss we revealed with calbindin whole-mount staining matches the pattern that we next observed with reporter expression in Purkinje-cell-specific fluorescent reporter mice.

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A combination of dynamic calbindin expression and staining artifacts can affect the visualization of Purkinje cells even in the absence of Purkinje cell loss. We observed striped calbindin expression in both young and aged C57Bl/J6 control mice (Figure 2—figure supplement 2A), possibly due to calcium dynamics. We confirmed that these stripes were not due to widespread Purkinje cell loss by staining adjacent tissue sections with Neutral Red, which revealed that the Purkinje cell bodies were still present (Figure 2—figure supplement 2A). In addition, in young and aged cerebellar tissue from C57Bl/J6 mice, the Purkinje cell dendrites span the molecular layer (Figure 2—figure supplement 2A), whereas in degenerating tissue, shrunken dendrites, thickened axons, and torpedoes can be observed (Figure 2A and B). Previous studies have shown that calbindin mRNA and protein are reduced in the cerebella of aged mice, rats, and humans (Iacopino and Christakos, 1990; Iacopino et al., 1990), and reduced calbindin immunoreactivity has been observed in surviving Purkinje cells in aged rats and in patients with spinocerebellar degeneration (Amenta et al., 1994; Ishikawa et al., 1995). Therefore, we argue that calbindin expression alone is not a reliable, sufficient indicator of Purkinje cell loss and should be supplemented with other histological and labeling techniques. Staining artifacts can also give the false appearance of Purkinje cell absence, but background staining or Neutral Red can reveal the Purkinje cells (Figure 2—figure supplement 2B). For this reason, we used multiple methods to visualize Purkinje cell degeneration and loss. Degenerative Purkinje cell pathology, multiple antibodies, Neutral Red staining, and a Purkinje-cell-specific genetically driven fluorescent reporter confirmed that the striped cellular pattern we observed indicates robust regional Purkinje cell loss in aged mice and that it arises due to neurodegeneration in a subpopulation of Purkinje cells.

The pattern of age-related Purkinje cell loss overlaps with but is distinct from the overall pattern of zebrin II expression

In mutant mice with Purkinje cell loss (leaner Fletcher et al., 1996), nervous (Edwards et al., 1994), BALB/c npc^nih (Sarna et al., 2003), C57BLKS/J spm (Sarna et al., 2003), Cacna1a null (Fletcher et al., 2001), and acid sphingomyelinase knockout (ASMKO) mice (Sarna et al., 2001), as well as mice with global brain ischemia (Welsh et al., 2002), neurodegeneration occurs according to the expression of zebrin II (Sarna and Hawkes, 2003). Zebrin II (an antigen on the aldolase C protein Ahn et al., 1994) is the most well-studied cerebellar patterning marker. In vertebrates, zebrin II expression reveals a striking pattern of parasagittal stripes across the cerebellar cortex (Sillitoe et al., 2005). Degeneration respects two main populations in the map as revealed by zebrin II expression; for example, in the nervous mutant mouse, Purkinje cell loss occurs selectively in zebrin II-positive Purkinje cells (Edwards et al., 1994), whereas in models of Niemann-Pick type C disease, zebrin II-negative Purkinje cells die first (Sarna et al., 2003). Aged mice displayed three distinct stripes of surviving Purkinje cells in the anterior vermis (Figure 1G–I), a pathology that resembles the pattern of zebrin II expression in young mice. Therefore, we asked whether the pattern of age-related Purkinje cell loss and survival indeed reflects the pattern of zebrin II expression. To test this, we cut coronal cerebellar tissue sections from aged mice (n=5) and immunostained them for calbindin (to label surviving Purkinje cells) and zebrin II (to reveal Purkinje cell stripe patterning), using cerebellar tissue from young mice (n=4) as controls.

In the anterior zone, age-related Purkinje cell loss respects the zebrin II boundaries. For example, in lobules III and IV, Purkinje cells began to degenerate selectively in zebrin II-negative stripes P1- and P2-, while the zebrin II-positive stripes remained intact (Figure 4B). In this region, calbindin and Purkinje-cell-specific reporter expression both reflect the same pattern of Purkinje cell loss with respect to zebrin II (Figure 4—figure supplement 1). In other regions, Purkinje cell loss forms clear stripes despite uniform zebrin II expression; for example, in lobule VI and anterior lobule VII, which are almost entirely zebrin II-positive, Purkinje cells degenerate in stripes (Figure 4B). This is in contrast to lobule VIII in the same mouse, which is unaffected by Purkinje cell degeneration despite the striped zebrin II expression in this lobule (Figure 4B). Interestingly, we observed differences in the relationship between age-related Purkinje cell loss and zebrin II expression within a single lobule. In dorsal lobule IX, Purkinje cell loss occurs in zebrin II-negative stripes, whereas in ventral lobule IX, Purkinje cell loss occurs in the medial zebrin II-positive stripe P1+ (Figure 4B). The paraflocculi display bands of Purkinje cell loss (Figure 4D), but given the heterogeneity of this region, with its developmentally defined Purkinje cell clusters and its stripes of intensely and weakly zebrin II-expressing Purkinje cells, and its complicated morphology (Fujita et al., 2012; Fujita et al., 2014), more detailed analysis is required to fully understand the relationship between this pattern and zebrin II expression. Taken together, these data show that although the pattern of age-related Purkinje cell loss can correspond with zebrin II expression – for example, in the anterior zone – the underlying pattern that dictates Purkinje cell loss during normal aging is more complicated than a single stripe marker would indicate. Instead, differential vulnerability to age-related neurodegeneration may result from complex interactions between Purkinje cell lineage, gene expression patterns, and specific functional properties. These distinct patterns in aged mice may uncover previously unidentified subsets within uniform zebrin II areas or provide clues into afferent fiber-to-Purkinje cell functional interactions that could influence long-term circuit function and health.

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Even during extreme Purkinje cell loss, with few Purkinje cells surviving throughout the cerebellum, a pattern of parasagittal stripes remains visible. This was evident in serial sections taken from a 25-month-old mouse and immunostained for calbindin, revealing the subsets of Purkinje cells that were most resistant to degeneration (Figure 5). The tissue sections displayed the same pattern of three parasagittal stripes in vermal lobules II through VI, although the width of the stripes was reduced, sometimes to one or two Purkinje cells per stripe. Most of Crus 1, the flocculi, and the paraflocculi had strong calbindin staining, indicating the presence of surviving Purkinje cells. Ventral lobule IX and lobule X were strikingly well preserved in comparison to the rest of the cerebellum. Even within regions with surviving Purkinje cells, the cells were undergoing degeneration. High magnification images of tissue from the 25-month-old mouse revealed extreme morphological abnormalities in Purkinje cells. Beaded recurrent axon collaterals formed plexuses where Purkinje cell somata likely used to be (Figure 6A–E), and Purkinje cell dendrites were thickened and fractured (Figure 6A and C). We also observed a putative recurrent axon collateral that extended to the top of the molecular layer in a large gap between surviving Purkinje cells (Figure 6E). These morphological abnormalities may represent the last efforts of surviving Purkinje cells to reside in an aged cerebellum where the majority of Purkinje cells have degenerated.

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Figure 6

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Light sheet imaging reveals a pattern of age-related Purkinje cell loss in the cerebellum

Light sheet imaging, when combined with tissue clearing, allows the visualization of labeled cells in multiple dimensions throughout a brain structure. Given the precise regional specificity of age-related Purkinje cell loss, we performed light sheet imaging of the cerebellum of an aged Purkinje-cell-specific fluorescent reporter mouse (Video 1) to fully visualize the pattern. Light sheet imaging revealed that lobule X is resistant to Purkinje cell loss during normal aging, similar to our observations of whole-mount cerebella immunostained for calbindin. Lobule X, the flocculi, and the paraflocculi comprise the nodular zone, a largely zebrin II-positive region (Figure 4C). The paraflocculi showed stripes of Purkinje cell loss during aging, as seen on calbindin-stained whole-mounts (Figure 4D). By combining the advantages of a Purkinje-cell-specific fluorescent reporter with the ability to reveal patterns within the core of the cerebellum (which are typically hard to appreciate due to the folding of the cortex), where antibodies do not always penetrate, light sheet imaging provides a complete picture of the pattern of age-related Purkinje cell loss.

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Taken together, our results from the whole-mount cerebella, coronal tissue sections, and light sheet imaging of Purkinje-cell-specific reporter expression indicate that despite some similarities, the pattern of age-related Purkinje cell loss is similar but not identical to the expression pattern of zebrin II, a reliable marker that defines the endogenous map of Purkinje cell stripes and zones.

Motor function is impaired in aged mice compared to young mice

Our results show that Purkinje cell loss during normal aging is extensive and occurs throughout the cerebellum. Despite this, the general motor behavior of our cohort of aged mice was ostensibly normal when the mice were observed in their home cages. To investigate the effect of age-related Purkinje cell loss on motor behavior more closely, we performed a series of behavioral tests, including the accelerating rotarod, the horizontal ladder, and analysis in a tremor monitor, on young and aged mice before sacrificing them and histologically examining the cerebella for Purkinje cell loss. We found that the aged mice (n=12) had a shorter latency to fall from the accelerating rotarod compared to the young mice (n=8; Figure 7B). Although the latency to fall was always lower in the aged mice compared to the young mice, the aged mice improved from day to day (Figure 7B), demonstrating their continued ability to learn new motor skills.

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Figure 7—source data 1

Source data for Figure 7.

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To test skilled, voluntary movement and limb control, we used a horizontal ladder task. Mice were subjected to an ‘easy’ trial, where every ladder rung was in place, and a ‘difficult’ trial, where every other ladder rung was removed. The number of footslips was recorded per trial. As expected, both the young (n=8) and aged (n=12) groups had more footslips during the difficult trial compared to during the easy trial (Figure 7C). However, we did not detect a significant difference in the number of footslips between the young and aged groups during either trial (Figure 7C).

Because humans and mice have increased tremor with age (Louis, 2019; White et al., 2016) and the cerebellum is implicated in tremor pathophysiology (Louis, 2016; Handforth, 2016; Cerasa and Quattrone, 2016), we used a custom-built tremor monitor to quantify tremor power and frequency (Brown et al., 2020). We found that aged mice (n=12) had significantly higher tremor power compared to young mice (n=11; Figure 7D). Peak power in both cohorts occurred at a frequency of ~10 Hz (Figure 7D), consistent with instances of pathological tremor being found within the frequency range of physiological tremor in mice (White et al., 2016; Brown et al., 2020).

We next wondered what structural and/or functional variables might contribute to the motor deficits observed in aged mice, using peak tremor power as an example. We tested whether peak power in aged mice (n=12) was influenced by body weight, relative age, or sex. Female aged mice tended to weigh less and have lower power tremor but still overlapped with male aged mice in terms of weight and peak tremor power (Figure 7—figure supplement 1A). We did not find a statistical correlation between peak tremor power, weight, or relative age (defined as the age of an individual mouse in comparison to other mice in the aged group; Figure 7—figure supplement 1B). This suggests that although aged mice have significantly increased tremor power compared to young mice (Figure 7D), neither weight nor differences in relative age among aged mice contribute significantly to tremor within the aged group. In other words, tremor does not necessarily worsen with increased age beyond a certain point within a given age range. This may be related to our finding that middle-aged mice can have Purkinje cell loss while some older mice do not (Table 1). Thus, aging is not a simple linear process in which increasing age is always negatively (or gradually) correlated with the loss of specific neural circuit functions and a decline in specific behaviors.

Given that not all aged mice have striped Purkinje cell loss, even within the same litter (Figure 1D–I; Table 1), we wondered whether aged mice without Purkinje cell loss performed better on motor tasks compared to aged mice with Purkinje cell loss. To address this, after behavioral testing, we collected cerebellar tissue sections from the aged mice and immunostained them with calbindin antibody. We subdivided the behavioral data of the aged mice based on whether they had Purkinje cell loss or not. We found that there was no significant difference in rotarod performance, number of footslips on the horizontal ladder, or tremor between aged mice with Purkinje cell loss and aged mice without Purkinje cell loss, though both aged groups had shorter latency to fall on the rotarod and an increased tremor power compared to young mice (Figure 7B’, C’ and D’). Together, these results suggest that while aged mice exhibit abnormalities in tremor and motor coordination, Purkinje cell loss alone, and specifically mild Purkinje cell loss, may not cause these behavioral impairments. Alternatively, Purkinje cell dysfunction, to varying degrees, may set a platform for the development of tremor and motor incoordination in aging mice, which could then co-initiate different abnormal behaviors with a given amount Purkinje cell loss.

Postmortem tissue from neurologically normal humans reveals age-related Purkinje cell degeneration with the coexistence of healthy and pathological cells

Reports that cerebellar volume is differentially impacted across lobules in human aging (Raz et al., 1998; Han et al., 2020; Bernard and Seidler, 2013; Luft et al., 1999; Hulst et al., 2015; Yu et al., 2017; Wang et al., 2024) prompted us to examine human cerebellar tissue at the cellular level to determine whether Purkinje cells exhibit differential vulnerability and resistance to age-related degeneration. We studied postmortem cerebellar tissue from three neurologically normal patients: a 21-year-old, a 57-year-old, and a 74-year-old. Using the calbindin antibody that effectively and reliably labels Purkinje cells in mice, on sagittal cut tissue sections through the vermis, we observed well-preserved Purkinje cells with expansive dendritic arbors in the tissue from the 21-year-old (Figure 8). In contrast, the immunostained tissue from the 74-year-old revealed extensive Purkinje cell loss that was observed as noticeable gaps in the Purkinje cell layer that were devoid of somata. In addition, we observed Purkinje cell dendrites with poor integrity and less span in their typically expansive architecture, a change that is indicative of retraction and degeneration of Purkinje cell dendrites (Figure 8), similar to our observations of Purkinje cells in aged mice (Figure 2A and B). Interestingly, the tissue from the 57-year-old represented an ‘intermediate’ stage with many robust healthy Purkinje cells that were flanked by areas with Purkinje cell dendrite deterioration and gaps in the Purkinje cell layer (Figure 8). These data imply the progressive degeneration and loss of Purkinje cells during human aging, as well as differential vulnerability and resistance to such loss among individual cells.

Figure 8

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We demonstrate that Purkinje cell loss that occurs during normal aging is not uniform. Instead, Purkinje cell loss occurs in a striking pattern of parasagittal stripes in aged mice. While this striped pattern bears some resemblance to the pattern of zebrin II expression, especially in the anterior zone lobules, the overall pattern is different from zebrin II expression, which typically defines the known stripe patterns of Purkinje cell loss in disease models. Furthermore, we show that aged mice have increased tremor power and deficits in rotarod performance compared to young mice but that performance on the horizontal ladder is preserved. Overall, we have found that age-related Purkinje cell loss occurs in a distinct striped pattern that may provide insight into the selective vulnerability and resistance of cells to neurodegeneration in the normal aging cerebellum.

All data generated or analyzed during this study are included in the manuscript and supporting files; source data files have been provided.

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Author details

1. Sarah G Donofrio

   1. Department of Pathology and Immunology, Baylor College of Medicine, Houston, United States
   2. Department of Neuroscience, Baylor College of Medicine, Houston, United States
   3. Cerebellum Science Center, Texas Children’s Hospital, Houston, United States
   4. Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, United States

   Contribution

   Conceptualization, Data curation, Formal analysis, Funding acquisition, Validation, Investigation, Visualization, Methodology, Writing – original draft, Writing – review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-1680-3302

2. Cheryl Brandenburg

   1. Department of Pathology and Immunology, Baylor College of Medicine, Houston, United States
   2. Cerebellum Science Center, Texas Children’s Hospital, Houston, United States
   3. Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, United States

   Contribution

   Conceptualization, Formal analysis, Investigation, Visualization, Methodology, Writing – review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-9370-2313

3. Amanda M Brown

   1. Department of Pathology and Immunology, Baylor College of Medicine, Houston, United States
   2. Cerebellum Science Center, Texas Children’s Hospital, Houston, United States
   3. Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, United States

   Contribution

   Resources, Formal analysis, Methodology, Writing – review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-1484-8972

4. Tao Lin

   1. Department of Pathology and Immunology, Baylor College of Medicine, Houston, United States
   2. Cerebellum Science Center, Texas Children’s Hospital, Houston, United States
   3. Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, United States

   Contribution

   Investigation, Methodology, Writing – review and editing

   Competing interests

   No competing interests declared

5. Hsiang-Chih Lu

   1. Department of Pathology and Immunology, Baylor College of Medicine, Houston, United States
   2. Cerebellum Science Center, Texas Children’s Hospital, Houston, United States
   3. Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, United States

   Contribution

   Resources, Methodology, Writing – review and editing

   Competing interests

   No competing interests declared

6. Roy V Sillitoe

   1. Department of Pathology and Immunology, Baylor College of Medicine, Houston, United States
   2. Department of Neuroscience, Baylor College of Medicine, Houston, United States
   3. Cerebellum Science Center, Texas Children’s Hospital, Houston, United States
   4. Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, United States
   5. Department of Pediatrics, Baylor College of Medicine, Houston, United States

   Contribution

   Conceptualization, Resources, Formal analysis, Supervision, Funding acquisition, Investigation, Writing – original draft, Project administration, Writing – review and editing

   For correspondence

   sillitoe@bcm.edu

   Competing interests

   Reviewing editor, eLife

   "This ORCID iD identifies the author of this article:" 0000-0002-6177-6190

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