The malleable brain: plasticity of neural circuits and behavior - a review from students to students.

One of the most intriguing features of the brain is its ability to be malleable, allowing it to adapt continually to changes in the environment. Specific neuronal activity patterns drive long-lasting increases or decreases in the strength of synaptic connections, referred to as long-term potentiation and long-term depression, respectively. Such phenomena have been described in a variety of model organisms, which are used to study molecular, structural, and functional aspects of synaptic plasticity. This review originated from the first International Society for Neurochemistry (ISN) and Journal of Neurochemistry (JNC) Flagship School held in Alpbach, Austria (Sep 2016), and will use its curriculum and discussions as a framework to review some of the current knowledge in the field of synaptic plasticity. First, we describe the role of plasticity during development and the persistent changes of neural circuitry occurring when sensory input is altered during critical developmental stages. We then outline the signaling cascades resulting in the synthesis of new plasticity-related proteins, which ultimately enable sustained changes in synaptic strength. Going beyond the traditional understanding of synaptic plasticity conceptualized by long-term potentiation and long-term depression, we discuss system-wide modifications and recently unveiled homeostatic mechanisms, such as synaptic scaling. Finally, we describe the neural circuits and synaptic plasticity mechanisms driving associative memory and motor learning. Evidence summarized in this review provides a current view of synaptic plasticity in its various forms, offers new insights into the underlying mechanisms and behavioral relevance, and provides directions for future research in the field of synaptic plasticity. Read the Editorial Highlight for this article on page 788. Cover Image for this issue: doi: 10.1111/jnc.13815.

9S1R nullomer peptide induces mitochondrial pathology, metabolic suppression, and enhanced immune cell infiltration, in triple-negative breast cancer mouse model.

Nullomers are the shortest strings of absent amino acid (aa) sequences in a species or group of species. Primes are those nullomers that have not been detected in the genome of any species. 9S1R is a 5-aa peptide prime sequence attached to 5-arginine aa, used to treat triple negative breast cancer (TNBC) in an in vivo mouse model. This unique peptide, administered with a trehalose carrier (9S1R-NulloPT), offers enhanced solubility and exhibits distinct anti-cancer effects against TNBC. In our study, we investigated the effect of 9S1R-NulloPT on tumor growth, metabolism, metastatic burden, tumor immune-microenvironment (TME), and transcriptome of aggressive mouse TNBC tumors. Notably, treated mice had smaller tumors in the initial phase of the treatment, as compared to untreated control, and diminished in vivo and ex vivo bioluminescence at later-stages - indicative of metabolically quiescent, dying tumors. The treatment also caused changes in TME with increased infiltration of immune cells and altered tumor transcriptome, with 365 upregulated genes and 710 downregulated genes. Consistent with in vitro data, downregulated genes were enriched in cellular metabolic processes (179), specifically mitochondrial TCA cycle/oxidative phosphorylation (44), and translation machinery/ribosome biogenesis (45). The upregulated genes were associated with the developmental (13), ECM organization (12) and focal adhesion pathways (7). In conclusion, our study demonstrates that 9S1R-NulloPT effectively reduced tumor growth during its initial phase, altering the TME and tumor transcriptome. The treatment induced mitochondrial pathology which led to a metabolic deceleration in tumors, aligning with in vitro observations.

Nullomer peptide increases immune cell infiltration and reduces tumor metabolism in triple negative breast cancer mouse model.

Background: Nullomers are the shortest strings of absent amino acid (aa) sequences in a species or group of species. Primes are those nullomers that have not been detected in the genome of any species. 9S1R is a 5-aa peptide derived from a prime sequence that is tagged with 5 arginine aa, used to treat triple negative breast cancer (TNBC) in an in vivo TNBC mouse model. 9S1R is administered in trehalose (9S1R-NulloPT), which enhances solubility and exhibits some independent effects against tumor growth and is thus an important component in the drug preparation. Method: We examined the effect of 9S1R-NulloPT on tumor growth, metabolism, metastatic burden, necrosis, tumor immune microenvironment, and the transcriptome of aggressive mouse TNBC tumors. Results: The peptide-treated mice had smaller tumors in the initial phase of the treatment, as compared to the untreated control, and reduced in vivo bioluminescence at later stages, which is indicative of metabolically inactive tumors. A decrease in ex vivo bioluminescence was also observed in the excised tumors of treated mice, but not in the secondary metastasis in the lungs. The treatment also caused changes in tumor immune microenvironment with increased infiltration of immune cells and margin inflammation. The treatment upregulated 365 genes and downregulated 710 genes in tumors compared to the untreated group. Consistent with in vitro findings in breast cancer cell lines, downregulated genes in the treated TNBC tumors include Cellular Metabolic Process Related genes (179), specifically mitochondrial genes associated with TCA cycle/oxidative phosphorylation (44), and translation machinery/ribosome biogenesis genes (45). Among upregulated genes, the Developmental Pathway (13), ECM Organization (12) and Focal Adhesion Related Pathways (7) were noteworthy. We also present data from a pilot study using a bilateral BC mouse model, which supports our findings. Conclusion: In conclusion, although 9S1R-NulloPT was moderate at reducing the tumor volume, it altered the tumor immune microenvironment as well as the tumor transcriptome, rendering tumors metabolically less active by downregulating the mitochondrial function and ribosome biogenesis. This corroborates previously published in vitro findings.

6-hydroxydopamine affects multiple pathways to induce cytotoxicity in differentiated LUHMES dopaminergic neurons.

The debilitating effects of Parkinson's disease (PD) progress over time and are pathophysiologically characterized by the formation of Lewy bodies due to the accumulation of α-synuclein aggregates resulting in the death of dopaminergic neurons. In the present study, we determined cell death pathways activated by acute exposure to 6-hydroxydopamine (6-OHDA) in differentiated LUHMES cells empirically followed by a 24 h toxin free interval, henceforth termed as washout/recovery period. Acute 6-OHDA exposure led to morphological changes in LUHMES cells and resulted in significant loss of neurite length and neurite thickness. Generation of reactive oxygen species and loss of mitochondrial membrane potential in the neuronal processes were persistent even after the recovery period. Our results show that 6-OHDA exposure leads to significant reduction in expression of mitochondrial OXPHOS complexes I, II, and IV and activation of caspase mediated apoptotic cell death cascade as observed by enhanced protein expression of cleaved-PARP-1 and cleaved-Caspase-3. Immunofluorescence microscopy approach confirmed that cell death occurs independent of the AIF translocation to the nucleus. Our experimental model, led to a ∼5-fold lower α-synuclein monomer expression and, interestingly, resulted in loss of protein ubiquitination in whole cell lysates. Altogether, this work provides evidence of multiple pathways targeted by 6-OHDA in differentiated LUHMES cells and expands research avenues for addressing the knowledge gap regarding the effect of 6-OHDA in the ubiquitin proteasome system for PD therapies.

Low Levels of Prohibitin in Substantia Nigra Makes Dopaminergic Neurons Vulnerable in Parkinson's Disease.

Since substantia nigra (SN) and ventral tegmental area (VTA) dopaminergic neurons are, respectively, susceptible or largely unaffected in Parkinson's disease (PD), we searched for protein(s) that regulates this differential sensitivity. Differentially, expressed proteins in SN and VTA were investigated employing two-directional gel electrophoresis- matrix-assisted laser desorption ionization time of flight (MALDI-TOF-TOF) analyses. Prohibitin, which is involved in mitochondrial integrity, was validated using immunoblot, qRT-PCR, and immunohistochemistry in normal mice as well as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-model, PD postmortem human brains, and PD cybrids. In prohibitin over-expression, differentiated SH-SY5Y neurons were investigated for their susceptibility to PD neurotoxin, 1-methyl-4-phenyl-pyridnium (MPP+). Prohibitin, Hsc73, and Cu-Zn superoxide dismutase (Cu-Zn SOD) were highly expressed in VTA, whereas heat shock protein A8 (HSPA8) and 14-3-3ζ/δ were 2-fold more in SN. Prohibitin level was transiently increased in SN but unaltered in VTA on the third day of MPTP-induced mice, whereas in PD human brains, prohibitin was depleted in both these regions. Parallel to mouse SN, an enhanced prohibitin expression was found in human PD cybrids. In MPP+-induced cellular model of PD, reduction in prohibitin level was found to be associated with a loss in its binding with Ndufs3, a mitochondrial complex I protein partner. Prohibitin over-expression resisted MPP+-induced neuronal death by restoring mitochondrial membrane potential, preventing reactive oxygen species generation and cytochrome c release into cytosol. These protective phenomena exerted by prohibitin over-expression altogether hinder caspase 3 activation induced by MPP+. These results imply that prohibitin is an important negotiator protein that regulates dopaminergic cell death in SN and their protection in VTA in PD.