Background: Excessive microglial activation is implicated in the pathogenesis of various age-related neurodegenerative diseases. In addition to neurons, brain-derived neurotrophic factor (BDNF) and its receptor TrkB are also expressed in microglia. However, the direct effect of BDNF on age-related microglial activation has rarely been investigated.Methods: We began to address this question by examining the effect of age on microglial activation and the BDNF-TrkB pathway in mice. By using pharmacological and genetic approaches, the roles of BDNF and downstream signaling pathways in microglial activation and related neurotoxicity were examined in microglial cell line and primary microglial cells.Results: We showed that microglial activation was evident in the brains of aged mice. The levels of BDNF and TrkB in microglia decreased with age and negatively correlated with their activation statuses in mice during aging. Interestingly, aging-related microglial activation could be reversed by chronic, subcutaneous perfusion of BDNF. Peripheral lipopolysaccharide (LPS) injection-induced microglial activation could be reduced by local supplement of BDNF, while shTrkB induced local microglial activation in naïve mice. In cultured microglial cell line and primary microglial cells, BDNF inhibited LPS-induced microglial activation, including morphological changes, activations of p38, JNK, and NF-кB, and productions of proinflammatory cytokines. These effects were blocked by shTrkB. BDNF induced activations of ErK and CREB which then competed with LPS-induced activation of NF-кB for binding to a common coactivator, CREB-binding protein.Conclusions: Decreasing BDNF-TrkB signaling during aging favors microglial activation, while upregulation BDNF signaling inhibits microglial activation via the TrkB-Erk-CREB pathway.

Adolescence is a time of developmental changes and reorganization in the brain. It has been hypothesized that stress has a greater neurological impact on adolescents than on adults. However, scientific evidence in support of this hypothesis is still limited. We treated adolescent (4-week-old) and adult (8-week-old) rats with social instability stress for five weeks and compared the subsequent structural and functional changes to amygdala neurons. In the stress-free control condition, the adolescent group showed higher fear-potentiated startle responses, larger dendritic arborization, more proximal dendritic spine distribution and lower levels of truncated TrkB than the adult rats. Social instability stress exerted opposite effects on fear-potentiated startle responses in these two groups, i.e., the stress period appeared to hamper the performance in adolescents but improved it in adult rats. Furthermore, whilst the chronic social stress applied to adolescent rats reduced their dendritic field and spine density in basal and lateral amygdala neurons, the opposite stress effects on neuron morphology were observed in the adult rats. Moreover, stress in adolescence suppressed the amygdala expression of synaptic proteins, i.e., full-length TrkB and SNAP-25, whereas, in the adult rats, chronic stress enhanced full-length and truncated TrkB expressions in the amygdala. In summary, chronic social instability stress hinders amygdala neuron development in the adolescent brain, while mature neurons in the amygdala are capable of adapting to the stress. The stress induced age-dependent effects on the fear-potentiated memory may occur by altering the BDNF-TrkB signaling and neuroplasticity in the amygdala.

Although many cardiovascular (CVD) medications, such as antithrombotics, statins, and antihypertensives, have been identified to treat atherosclerosis, at most, many of these therapeutic agents only delay its progression. A growing body of evidence suggests physical exercise could be implemented as a non-pharmacologic treatment due to its pro-metabolic, multisystemic, and anti-inflammatory benefits. Specifically, it has been discovered that certain anti-inflammatory peptides, metabolites, and RNA species (collectively termed “exerkines”) are released in response to exercise that could facilitate these benefits and could serve as potential therapeutic targets for atherosclerosis. However, much of the relationship between exercise and these exerkines remains unanswered, and there are several challenges in the discovery and validation of these exerkines. This review primarily highlights major anti-inflammatory exerkines that could serve as potential therapeutic targets for atherosclerosis. To provide some context and comparison for the therapeutic potential of exerkines, the anti-inflammatory, multisystemic benefits of exercise, the basic mechanisms of atherosclerosis, and the limited efficacies of current anti-inflammatory therapeutics for atherosclerosis are briefly summarized. Finally, key challenges and future directions for exploiting these exerkines in the treatment of atherosclerosis are discussed.

Parkinson’s disease (PD) is an age-related neurodegenerative disease caused by a selective loss of dopaminergic (DA) neurons in the substantia nigra (SN). Microglial activation is implicated in the pathogenesis of PD. This study aimed to characterize the role of microglial activation in aging-related nigral DA neuron loss and motor deficits in mice. We showed that, compared to 3-month-old mice, the number of DA neurons in the SN and the expression of dopamine transporter (DAT) in the striatum decreased during the period of 9 to 12 months of age. Motor deficits and microglial activation in the SN were also evident during these months. The number of DA neurons was negatively correlated with the degrees of microglial activation. The inhibition of age-related microglial activation by ibuprofen during these 3 months decreased DA neuron loss in the SN. Eliminating the microglia prevented systemic inflammation-induced DA neuron death. Forcing mice to run during these 3 months inhibited microglial activation and DA neuron loss. Blocking the brain-derived neurotrophic factor (BDNF) signaling eliminated the exercise-induced protective effects. In conclusion, nigral DA neurons were susceptible to local microglial activation. Running exercise upregulated BDNF-TrkB signaling and inhibited microglial activation during aging. Long-term exercise can be considered as a non-pharmacological strategy to ameliorate microglial activation and related neurodegeneration.

Multiphoton excited fluorescence (MPEF) microscopy is commonly adopted in academic studies, medical diagnoses, and industrial applications. The natural optical sectioning ability, due to the nonlinear phenomenon of multiphoton absorption via a high numerical aperture (NA) objective that focuses and generates a strong local electromagnetic field, could achieve micron/submicron spatial resolution and reconstruct three-dimensional (3D) fluorescence images for bio-structural analysis.^{1 – 4} The excitation wavelength of an ultrafast laser was chosen in the near-infrared region and low-absorption spectral window of a biological specimen so that MPEF microscopy could achieve a deep penetration depth in thick tissue. Furthermore, with the second-harmonic generation (SHG) signal that directly reveals highly polarizable molecules and non-centrosymmetric structures, the distribution of collagen and myosin could be imaged in the biospecimen without any staining needed.^{5 – 7} These advantages make MPEF and SHG suitable for in vitro and in vivo applications, such as imaging cortical vasculature or neuronal activities inside a mouse brain,^{8 – 11} high-resolution ophthalmoscope imaging for cellular retina structures,¹² muscle disease measurement,^{13 – 15} and skin disease diagnosis.¹⁶ Based on the multiphoton excitation mechanism, temporal focusing can accommodate widefield and fast MPEF imaging due to the high-throughput illumination and detection ability.^17,18 The diffraction element (e.g., a blazed grating) in temporal focusing multiphoton microscopy (TFMPM) is utilized for generating angular dispersion to separate different spectral components into different angles according to a diffraction equation. After passing through the $4\text{-}f$ imaging system, which consists of a collimating lens and objective lens, the spectral components overlap in phase to achieve temporal focusing on the focal plane of the objective. The broadened laser pulse is reconstructed to its original short pulse width to have sufficient peak power for widefield MPEF and SHG, and is less time-consuming than conventional point scanning microscopy.^{19 – 22} The axial excitation confinement (AEC) of TFMPM can achieve a few microns and depends on several system parameters, including the transform-limited pulse width, laser beam size, groove density of the diffraction grating, optical system magnification, and NA of the objective lens.^{23 – 26} With different modified system configurations, TFMPM is capable of various applications. For example, the fast 3D Brownian motion of beads can be directly tracked,^{27 – 29} and the neural activity of mouse can be analyzed with fast volumetric imaging.^{30 – 33} A heterodyne detection mechanism has been used for parallelized frequency-domain 3D fast fluorescence lifetime image measurement.³⁴ TFMPM has also been successfully combined with optical tweezers for particle and cell trapping.³⁵ Widefield multiphoton-induced ablation using high laser-pulse energy fluence in a TFMPM system has been demonstrated for chicken tendon machining, after which SHG imaging could be directly performed to view the machined tendon structure.³⁶ Furthermore, an intensity mask can be integrated with the TFMPM for fast pattern machining and axially resolved microfabrication with various materials, including photoresist,³⁷ bovine serum albumin,³⁸ graphene oxide,³⁹ and metal substrates.⁴⁰ The desired intensity pattern can also be generated from a high-resolution phase mask applied by a liquid-crystal spatial-light modulator.^{41 – 43} A phase-contrast filter can be adopted to directly transform the phase mask into an intensity pattern to probe arbitrarily neural bodies or dendrites.³⁰

There has been increasing evidence that consumption of dietary supplements or specific nutrients can influence cognitive processes and emotions. A proprietary chicken meat extraction, Chicken Meat Ingredient-168 (CMI-168), has previously been shown to enhance cognitive function in humans. However, the mechanism underlying the CMI-168-induced benefits remains unclear. In this study, we investigated the effects of CMI-168 on hippocampal neuroplasticity and memory function in middle-aged (9–12 months old) mice. The mice in the test group (termed the “CMI-168 group”) were fed dietary pellets produced by mixing CMI-168 and normal laboratory mouse chow to provide a daily CMI-168 dose of 150 mg/kg of body weight for 6 weeks. The control mice (termed the “Chow group”) were fed normal laboratory mouse chow pellets. CMI-168 supplementation did not affect the body weight gain, food intake, or exploratory behavior of the mice. In the novel object recognition test, the CMI-168 group showed better hippocampus-related non-spatial memory compared to the control Chow group. However, spatial memory examined by the Morris Water Maze test was similar between the two groups. There was also no significant difference in the induction and maintenance of long-term potentiation and dendritic complexity of the hippocampal cornu ammonis region 1 (CA1) neurons, as well as the levels of neuroplasticity-related proteins in the hippocampi of the CMI-168 and Chow groups. Interestingly, we observed that CMI-168 appeared to protect the mice against stress-induced weight loss. In conclusion, dietary supplementation of CMI-168 was found to improve learning and memory in middle-aged mice, independent of structural or functional changes in the hippocampus. The resilience to stress afforded by CMI-168 warrants further investigation.