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Article: The multiple roles of GH in neural ageing and injury.

Blackmore, Daniel G / Waters, Michael J

2023 Volume 17, Page(s) 1082449

Abstract: Advanced age is typically associated with a decrease in cognitive function including impairment in the formation and retention of new memories. The hippocampus is critical for learning and memory, especially spatial learning, and is particularly affected ...

Abstract	Advanced age is typically associated with a decrease in cognitive function including impairment in the formation and retention of new memories. The hippocampus is critical for learning and memory, especially spatial learning, and is particularly affected by ageing. With advanced age, multiple neural components can be detrimentally affected including a reduction in the number of neural stem and precursor cells, a decrease in the formation of adult born neurons (neurogenesis), and deficits in neural circuitry, all of which ultimately contribute to impaired cognitive function. Importantly, physical exercise has been shown to ameliorate many of these impairments and is able to improve learning and memory. Relevantly, growth hormone (GH) is an important protein hormone that decreases with ageing and increases following physical exercise. Originally described due to its role in longitudinal growth, GH has now been identified to play several additional key roles, especially in relation to the brain. Indeed, the regular decrease in GH levels following puberty is one of the most well documented components of neuroendocrine ageing. Growth hormone deficiency (GHD) has been described to have adverse effects on brain function, which can be ameliorated
Language	English
Publishing date	2023-03-07
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2411902-7
ISSN	1662-453X ; 1662-4548
ISSN (online)	1662-453X
ISSN	1662-4548
DOI	10.3389/fnins.2023.1082449
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Article ; Online: The Active Place Avoidance (APA) Test, an Effective, Versatile and Repeatable Spatial Learning Task for Mice.

Ali, Asad A / Walker, Tara L / Blackmore, Daniel G

Journal of visualized experiments : JoVE

2024 , Issue 204

Abstract: Hippocampus-dependent spatial learning in rodents has been tested using a variety of methods. These include the Morris water maze (MWM), Y-maze, and novel object location (NOL) tasks. More recently, the active place avoidance (APA) task has been ... ...

Abstract	Hippocampus-dependent spatial learning in rodents has been tested using a variety of methods. These include the Morris water maze (MWM), Y-maze, and novel object location (NOL) tasks. More recently, the active place avoidance (APA) task has been developed as an alternative to these more traditional approaches. In the APA task, mice must use spatial cues placed around a rotating arena to avoid a stationary shock zone. Due to the multiple parameters that can be adjusted, the APA task has been demonstrated to be a very versatile approach. It lends itself to being used longitudinally and repeatedly for the same cohort of mice. Here, we provide a detailed protocol to successfully conduct the APA task. We also highlight alternative APA approaches that can be used to examine different components of spatial learning. We describe the data collection and analysis processes. Critical steps during the APA task are discussed to increase the likelihood of successfully conducting the test. The APA task has several advantages over more traditional spatial navigation tests. It is appropriate to use with aged mice or those with disease phenotypes such as Alzheimer's disease. The complexity of the task can be easily altered, allowing a wide range of mouse strains to be tested. Further, the APA task is suitable for testing animals that have undergone surgery or experimental interventions that may have affected motor or neural function, such as stroke or traumatic brain injury.
MeSH term(s)	Humans ; Animals ; Mice ; Spatial Learning ; Alzheimer Disease ; Brain Injuries, Traumatic ; Cues ; Data Collection
Language	English
Publishing date	2024-02-16
Publishing country	United States
Document type	Journal Article ; Video-Audio Media
ZDB-ID	2259946-0
ISSN	1940-087X ; 1940-087X
ISSN (online)	1940-087X
ISSN	1940-087X
DOI	10.3791/65935
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Article ; Online: Ultrasound as a versatile tool for short- and long-term improvement and monitoring of brain function.

Blackmore, Daniel G / Razansky, Daniel / Götz, Jürgen

Neuron

2023 Volume 111, Issue 8, Page(s) 1174–1190

Abstract: Treating the brain with focused ultrasound (FUS) at low intensities elicits diverse responses in neurons, astroglia, and the extracellular matrix. In combination with intravenously injected microbubbles, FUS also opens the blood-brain barrier (BBB) and ... ...

Abstract	Treating the brain with focused ultrasound (FUS) at low intensities elicits diverse responses in neurons, astroglia, and the extracellular matrix. In combination with intravenously injected microbubbles, FUS also opens the blood-brain barrier (BBB) and facilitates focal drug delivery. However, an incompletely understood cellular specificity and a wide parameter space currently limit the optimal application of FUS in preclinical and human studies. In this perspective, we discuss how different FUS modalities can be utilized to achieve short- and long-term improvements, thereby potentially treating brain disorders. We review the ongoing efforts to determine which parameters induce neuronal inhibition versus activation and how mechanoreceptors and signaling cascades are activated to induce long-term changes, including memory improvements. We suggest that optimal FUS treatments may require different FUS modalities and devices, depending on the targeted brain area or local pathology, and will be greatly enhanced by new techniques for monitoring FUS efficacy.
MeSH term(s)	Rats ; Animals ; Humans ; Rats, Sprague-Dawley ; Blood-Brain Barrier/diagnostic imaging ; Brain/diagnostic imaging ; Ultrasonography ; Biological Transport ; Drug Delivery Systems/methods
Language	English
Publishing date	2023-03-13
Publishing country	United States
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	808167-0
ISSN	1097-4199 ; 0896-6273
ISSN (online)	1097-4199
ISSN	0896-6273
DOI	10.1016/j.neuron.2023.02.018
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Article ; Online: Protocol for three alternative paradigms to test spatial learning and memory in mice.

Blackmore, Daniel G / Brici, David / Walker, Tara L

STAR protocols

2022 Volume 3, Issue 3, Page(s) 101500

Abstract: Here, we describe three alternative paradigms to overcome the limitations of the most widely used spatial learning paradigm for rodents: the Morris water maze. We outline the preparation of behavioral testing rooms and mouse handling/habituation prior to ...

Abstract	Here, we describe three alternative paradigms to overcome the limitations of the most widely used spatial learning paradigm for rodents: the Morris water maze. We outline the preparation of behavioral testing rooms and mouse handling/habituation prior to testing. We then detail three spatial learning and memory tasks: the Barnes maze, active place avoidance, and novel object location tasks. These tests have been successfully used across multiple ages (from 2 to 24 months) in both wild-type and transgenic animals. For complete details on the use and execution of this protocol, please refer to Leiter et al. (2022).
MeSH term(s)	Animals ; Maze Learning ; Memory ; Mice ; Mice, Inbred C57BL ; Spatial Learning
Language	English
Publishing date	2022-06-23
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	2666-1667
ISSN (online)	2666-1667
DOI	10.1016/j.xpro.2022.101500
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Article: Ultrasound-Mediated Bioeffects in Senescent Mice and Alzheimer's Mouse Models.

Balbi, Matilde / Blackmore, Daniel G / Padmanabhan, Pranesh / Götz, Jürgen

Brain sciences

2022 Volume 12, Issue 6

Abstract: Ultrasound is routinely used for a wide range of diagnostic imaging applications. However, given that ultrasound can operate over a wide range of parameters that can all be modulated, its applicability extends far beyond the bioimaging field. In fact, ... ...

Abstract	Ultrasound is routinely used for a wide range of diagnostic imaging applications. However, given that ultrasound can operate over a wide range of parameters that can all be modulated, its applicability extends far beyond the bioimaging field. In fact, the modality has emerged as a hybrid technology that effectively assists drug delivery by transiently opening the blood-brain barrier (BBB) when combined with intravenously injected microbubbles, and facilitates neuromodulation. Studies in aged mice contributed to an insight into how low-intensity ultrasound brings about its neuromodulatory effects, including increased synaptic plasticity and improved cognitive functions, with a potential role for neurogenesis and the modulation of NMDA receptor-mediated neuronal signalling. This work is complemented by studies in mouse models of Alzheimer's disease (AD), a form of pathological ageing. Here, ultrasound was mainly employed as a BBB-opening tool that clears protein aggregates via microglial activation and neuronal autophagy, thereby restoring cognition. We discuss the currently available ultrasound approaches and how studies in senescent mice are relevant for AD and can accelerate the application of low-intensity ultrasound in the clinic.
Language	English
Publishing date	2022-06-13
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2651993-8
ISSN	2076-3425
ISSN	2076-3425
DOI	10.3390/brainsci12060775
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Article ; Online: Exercise reverses learning deficits induced by hippocampal injury by promoting neurogenesis.

Codd, Lavinia N / Blackmore, Daniel G / Vukovic, Jana / Bartlett, Perry F

Scientific reports

2020 Volume 10, Issue 1, Page(s) 19269

Abstract: Hippocampal atrophy and cognitive decline are common sequelae of many neurodegenerative disorders, including stroke. To determine whether cognitive decline can be ameliorated by exercise-induced neurogenesis, C57BL/6 mice in which a unilateral ... ...

Abstract	Hippocampal atrophy and cognitive decline are common sequelae of many neurodegenerative disorders, including stroke. To determine whether cognitive decline can be ameliorated by exercise-induced neurogenesis, C57BL/6 mice in which a unilateral hippocampal injury had been induced by injecting the vasoconstrictor endothelin-1 into their right hippocampus, were run voluntarily for 21 days on a running-wheel. We found the severe deficits in spatial learning, as detected by active place-avoidance task, following injury were almost completely restored in animals that ran whereas those that did not run showed no improvement. We show the increase in neurogenesis found in both the injured and contralateral hippocampi following running was responsible for the restoration of learning since bilateral ablation of newborn doublecortin (DCX)-positive neurons abrogated the cognitive improvement, whereas unilateral ablations of DCX-positive neurons did not prevent recovery, demonstrating that elevated neurogenesis in either the damaged or intact hippocampus is sufficient to reverse hippocampal injury-induced deficits.
MeSH term(s)	Animals ; Hippocampus/injuries ; Hippocampus/physiopathology ; Learning Disabilities/physiopathology ; Learning Disabilities/therapy ; Mice ; Mice, Transgenic ; Neurogenesis ; Physical Conditioning, Animal
Language	English
Publishing date	2020-11-06
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-020-76176-1
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Article ; Online: Platelet-derived exerkine CXCL4/platelet factor 4 rejuvenates hippocampal neurogenesis and restores cognitive function in aged mice.

Leiter, Odette / Brici, David / Fletcher, Stephen J / Yong, Xuan Ling Hilary / Widagdo, Jocelyn / Matigian, Nicholas / Schroer, Adam B / Bieri, Gregor / Blackmore, Daniel G / Bartlett, Perry F / Anggono, Victor / Villeda, Saul A / Walker, Tara L

Nature communications

2023 Volume 14, Issue 1, Page(s) 4375

Abstract: The beneficial effects of physical activity on brain ageing are well recognised, with exerkines, factors that are secreted into the circulation in response to exercise, emerging as likely mediators of this response. However, the source and identity of ... ...

Abstract	The beneficial effects of physical activity on brain ageing are well recognised, with exerkines, factors that are secreted into the circulation in response to exercise, emerging as likely mediators of this response. However, the source and identity of these exerkines remain unclear. Here we provide evidence that an anti-geronic exerkine is secreted by platelets. We show that platelets are activated by exercise and are required for the exercise-induced increase in hippocampal precursor cell proliferation in aged mice. We also demonstrate that increasing the systemic levels of the platelet-derived exerkine CXCL4/platelet factor 4 (PF4) ameliorates age-related regenerative and cognitive impairments in a hippocampal neurogenesis-dependent manner. Together these findings highlight the role of platelets in mediating the rejuvenating effects of exercise during physiological brain ageing.
MeSH term(s)	Animals ; Mice ; Blood Platelets ; Cognition ; Hippocampus ; Immunologic Factors ; Neurogenesis ; Platelet Factor 4 ; Aging ; Cognitive Dysfunction
Chemical Substances	Immunologic Factors ; Platelet Factor 4 (37270-94-3)
Language	English
Publishing date	2023-08-16
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-023-39873-9
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Article ; Online: Ubiquitination of the GluA1 Subunit of AMPA Receptors Is Required for Synaptic Plasticity, Memory, and Cognitive Flexibility.

Guntupalli, Sumasri / Park, Pojeong / Han, Dae Hee / Zhang, Lingrui / Yong, Xuan Ling Hilary / Ringuet, Mitchell / Blackmore, Daniel G / Jhaveri, Dhanisha J / Koentgen, Frank / Widagdo, Jocelyn / Kaang, Bong-Kiun / Anggono, Victor

The Journal of neuroscience : the official journal of the Society for Neuroscience

2023 Volume 43, Issue 30, Page(s) 5448–5457

Abstract: Activity-dependent changes in the number of AMPA-type glutamate receptors (AMPARs) at the synapse underpin the expression of LTP and LTD, cellular correlates of learning and memory. Post-translational ubiquitination has emerged as a key regulator of the ... ...

Abstract	Activity-dependent changes in the number of AMPA-type glutamate receptors (AMPARs) at the synapse underpin the expression of LTP and LTD, cellular correlates of learning and memory. Post-translational ubiquitination has emerged as a key regulator of the trafficking and surface expression of AMPARs, with ubiquitination of the GluA1 subunit at Lys-868 controlling the post-endocytic sorting of the receptors into the late endosome for degradation, thereby regulating their stability at synapses. However, the physiological significance of GluA1 ubiquitination remains unknown. In this study, we generated mice with a knock-in mutation in the major GluA1 ubiquitination site (K868R) to investigate the role of GluA1 ubiquitination in synaptic plasticity, learning, and memory. Our results reveal that these male mice have normal basal synaptic transmission but exhibit enhanced LTP and deficits in LTD. They also display deficits in short-term spatial memory and cognitive flexibility. These findings underscore the critical roles of GluA1 ubiquitination in bidirectional synaptic plasticity and cognition in male mice.
MeSH term(s)	Mice ; Male ; Animals ; Receptors, AMPA/metabolism ; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid/metabolism ; Neuronal Plasticity/physiology ; Synapses/physiology ; Receptors, Glutamate/metabolism ; Ubiquitination ; Cognition ; Hippocampus/metabolism
Chemical Substances	Receptors, AMPA ; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (77521-29-0) ; Receptors, Glutamate
Language	English
Publishing date	2023-07-07
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	604637-x
ISSN	1529-2401 ; 0270-6474
ISSN (online)	1529-2401
ISSN	0270-6474
DOI	10.1523/JNEUROSCI.1542-22.2023
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Article ; Online: Selective Ablation of BDNF from Microglia Reveals Novel Roles in Self-Renewal and Hippocampal Neurogenesis.

Harley, Samuel B R / Willis, Emily F / Shaikh, Samreen N / Blackmore, Daniel G / Sah, Pankaj / Ruitenberg, Marc J / Bartlett, Perry F / Vukovic, Jana

The Journal of neuroscience : the official journal of the Society for Neuroscience

2021 Volume 41, Issue 19, Page(s) 4172–4186

Abstract: Microglia, the resident immune cells of the CNS, have emerged as key regulators of neural precursor cell activity in the adult brain. However, the microglia-derived factors that mediate these effects remain largely unknown. In the present study, we ... ...

Abstract	Microglia, the resident immune cells of the CNS, have emerged as key regulators of neural precursor cell activity in the adult brain. However, the microglia-derived factors that mediate these effects remain largely unknown. In the present study, we investigated a role for microglial brain-derived neurotrophic factor (BDNF), a neurotrophic factor with well known effects on neuronal survival and plasticity. Surprisingly, we found that selective genetic ablation of BDNF from microglia increased the production of newborn neurons under both physiological and inflammatory conditions (e.g., LPS-induced infection and traumatic brain injury). Genetic ablation of BDNF from microglia otherwise also interfered with self-renewal/proliferation, reducing their overall density. In conclusion, we identify microglial BDNF as an important factor regulating microglia population dynamics and states, which in turn influences neurogenesis under both homeostatic and pathologic conditions.
MeSH term(s)	Animals ; Brain-Derived Neurotrophic Factor/genetics ; Cell Proliferation ; Cell Survival/genetics ; Dendrites/ultrastructure ; Dendritic Spines/ultrastructure ; Encephalitis/chemically induced ; Encephalitis/pathology ; Hippocampus/physiology ; Learning/physiology ; Memory/physiology ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Microglia/metabolism ; Nerve Regeneration/genetics ; Nerve Regeneration/physiology ; Neural Stem Cells/physiology ; Neural Stem Cells/ultrastructure ; Neurogenesis/genetics ; Neurogenesis/physiology
Chemical Substances	Bdnf protein, mouse ; Brain-Derived Neurotrophic Factor
Language	English
Publishing date	2021-03-30
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	604637-x
ISSN	1529-2401 ; 0270-6474
ISSN (online)	1529-2401
ISSN	0270-6474
DOI	10.1523/JNEUROSCI.2539-20.2021
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Article ; Online: Distribution of neural precursor cells in the adult mouse brain.

Blackmore, Daniel G / Rietze, Rodney L

Methods in molecular biology (Clifton, N.J.)

2013 Volume 1059, Page(s) 183–194

Abstract: Since its inception in 1992 [Reynolds and Weiss, Science 255:1707-10, 1992], the neurosphere assay (NSA) has proven an exceptionally useful tool in detecting neural stem cells (NSCs) in both the developing and adult mammalian brain. To date, over 1,300 ... ...

Abstract	Since its inception in 1992 [Reynolds and Weiss, Science 255:1707-10, 1992], the neurosphere assay (NSA) has proven an exceptionally useful tool in detecting neural stem cells (NSCs) in both the developing and adult mammalian brain. To date, over 1,300 manuscripts have been published employing the assay, attesting to the robustness of the assay, and its ease of use. However, a brief survey of the literature demonstrates that the number of primary neurospheres generated from essentially the same anatomical region (i.e., the periventricular region of the rostral lateral ventricle) ranges between 150 and 936 [Gritti et al., J Neurosci 22:437-445, 2002; Tropepe et al., J Neurosci 17:7850-59, 1997; Doetsch et al., Cell 97:703-16, 1999; Enwere et al., J Neurosci 24:8354-65, 2004]. Indeed, in our hands we typically generate approximately 1,800 primary spheres when harvesting tissue from the same region.
MeSH term(s)	Animals ; Brain/cytology ; Cell Culture Techniques ; Dissection ; Mice ; Mice, Inbred C57BL ; Microtomy ; Neural Stem Cells/physiology ; Organ Specificity ; Spheroids, Cellular
Language	English
Publishing date	2013
Publishing country	United States
Document type	Journal Article
ISSN	1940-6029
ISSN (online)	1940-6029
DOI	10.1007/978-1-62703-574-3_16
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