Извилистость пути -путь на вершину горы извилист независимо

Извилистость пути -путь на вершину горы извилист, независимо от того, улитка ты или великан – говорила мудрая улитка, ползущая на вершину Фудзиямы -The way to the top of the mountain is not straight, and it does not depend on whether you are the snail or a giant – said the snail moving to the top of Fudziyama ТИХО ПОЛЗИ, УЛИТКА ВВЕРХ ПО СКЛОНУ ФУДЗИ ВВЕРХ ДО САМЫХ ВЫСОТ Slowly, slowly crawl, the snail Up the Fudzi slope Up to the very top

Молекула памяти: мифы и реальность P. BALABAN Institute of Higher Nervous Activity and Neurophysiology, Russian Academy of Sciences

The principal question of developmental neuroscience is how during development 1012 neurons establish 1015 specific synaptic connections to produce our functional thinking brain genes activity “critical periods”

Visual illustration of 2 patterns P. Bonifazi SPA GDP

All developmental steps are activity dependent and insult sensitive 10 15 synapses Genes Des unités fonctionnelles Environment V IV Formation de réseaux III Formation de synapses II MIGRATION 0 synapse I PROLIFERATION Environmental Genetic Insults

Как возникает и где хранится информация об изменении активности в синапсах?

How to identify the conductor/first solist?

The Terminal of the Cerebral Side Branch of the CGC Axon Is a Presynaptic Zone Potentially Affected by Learning-Induced Nonsynaptic Plasticity The proposed mechanism of ‘‘remotecontrolled’’ increase in synaptic efficacy after classical conditioning in Lymnaea. In naive animals, application of amyl acetate (used as the conditioned stimulus [CS] during training) leads to a small increase in the tonic firing rate of the cerebral giant cell (CGC, cartoon trace on top). Spikes evoked by the CS in putative chemosensory neurons (SN) of the lip only evoke small excitatory postsynaptic potentials in the command-like cerebral-to-buccal interneurons (CBI) of the feeding system. In conditioned animals, the CGC soma and proximal axonal segments are persistently depolarized Nikitin, Balaban, Kemenes, Current Biology, 2013

Suppression of a Potassium A Current Reduces the Attenuation of Calcium Transients and Spikes in the Cerebral Side Branch of the CGC (A) The inactivation curve of the potassium A current (IA) of the CGC Inset: CGC MP values (mean 6 SEM) from preparations from control (blue lines) and trained animals (red lines) plotted on the relevant section of the inactivation curve. (Bi) Comparison of the ratios of the calcium signal amplitudes measured at the most proximal (1) and most distal (3) regions of interest (ROIs; see bottom panel) in a preparation from a naïve control animal before and after 4 -AP treatment. Dashed lines indicate baseline levels and the peak of the calcium transient in ROI 1, respectively. Solid line indicates the peak of the calcium transient in ROI 3. The electrophysiologically recorded soma spikes that triggered the axonal calcium transients (recorded with Oregon green) are also shown. (Bii) The ratio (mean 6 SEM values from eight preparations) is significantly higher after the application of 4 -AP (p < 0. 05). (C) Attenuation of spikes in the cerebral side branch of the CGC and its reduction by 4 -AP recorded with the voltage-sensitive dye JPW 1114. .

LEARNING Stim. 1 CS R 1 Stim. 2 Stim. 3 UCS R 2 R 3

Stim. 1 CS R 1 Stim. 2 Stim. 3 UCS R 2 R 3

SENSORY NEURON Malyshev, Balaban J. Neurophysiol. , 2002

CONFOCAL MICROSCOPY OF SYNAPTIC CONTACT ZONE BETWEEN IDENTIDFIED SNAIL NEURONS PRESYNAPTIC NEURON NEURITES OF POSTSYNAPTIC NEURONS

SEROTONERGIC NEURON LPa 3 RPa 3 +BAPTA Withdrawal behavior interneurons

DIFFERENCE, CONTROL-BAPTA Balaban et al. , 2004, Europ. J. Neuroscience

PLACTICITY LOCUS Glutamate WITHDRAWAL INTERNEURON

Mechanisms of synaptic plasticity: pre- post- retrograde +

PKmζ Protein Kinase M zeta Constitutively active isoform of Protein Kinase C (PKC) Functions in the storage of memory.

МОЖНО ЛИ «Нью-Йорк таймс» торжественно объявила, СТЕРЕТЬ ПАМЯТЬ? В марте 2009 года газета что ученые из Медицинского центра в Бруклине под руководством доктора Сактора открыли «молекулу памяти» , воздействуя на которую можно будет вскоре стирать в мозгу человека любое нежелательное ему воспоминание, тем самым облегчая ему всю последующую жизнь. Фермент протеинкиназа М-зета считается одним из ключевых элементов механизма долговременной памяти (это было установлено несколько лет назад), однако более всего он — если верить авторам — интересен тем, что с его помощью сохраняются только комплексные воспоминания, детальная информация о совершенных действиях и пережитых потрясениях. Следовательно, при выборочном уничтожении молекул протеинкиназы М-зета человек может «забыть» о неугодных ему событиях и переживаниях, причем функционирование его мозга не нарушится.

Effect of ZIP on very long-term CTA memory in the insular cortex. (A) ZIP/vehicle were administered 3 mo after training, and memory was tested 2 d later. The dashed line indicates equal preference for the CS and water, i. e. , AI = 50. (B) ZIP/vehicle/scrambled ZIP were administered 1 mo after training, and memory was tested 12 d later. Saccharin was the CS in both A and B.

PKMζ formation in LTP. The protein kinase C, zeta (PRKCZ) gene has two promoters, one producing a full-length protein kinase Cζ (PKCζ) from exons encoding a regulatory domain (Reg; shown in red) and a catalytic domain (Cat; shown in green). In neurons, an internal promoter produces a protein kinase Mζ (PKMζ) m. RNA that encodes a ζ catalytic domain without a regulatory domain. The PKMζ m. RNA is transported to dendrites and is translationally repressed by PIN 1 (protein interacting with NIMA 1). During long-term potentiation induction, multiple signalling pathways stimulated by NMDAR activation are required to release the translational block. Once synthesized, PKMζ binds to and is phosphorylated by phosphoinositide-dependent protein kinase 1 (PDK 1), which increases the constitutive kinase activity of PKMζ then initiates a positive feedback loop through inhibition of PIN 1 to maintain increased dendritic translation of the PKMζ message. PKMζ potentiates AMPAR responses by increasing the number of the receptors in the postsynaptic density through the action of the trafficking protein N-ethylmaleimide-sensitive factor (Ns. F). Ca. MKII, Ca 2+/calmodulin-dependent protein kinase II; glu, glutamate; MAPK, mitogenactivated protein kinase; m. To. R, mammalian target of rapamycin; PI 3 K, phosphatidylinositol 3 kinase; PKA, protein kinase A

Model of PKM’s role in maintaining long-term synaptic enhancement

Stim. 1 CS R 1 Stim. 2 Stim. 3 UCS R 2 R 3

Consolidation – a hypothetical process that occurs immediately after the initial acqusition of a memory during which the long-term memory is thought to be forming and stabilizing. Reconsolidation – even more hypothetical process that suggests a possibility for longterm memory to re-enter a consolidation phase when

Protocol of context conditioning experiment (A) with anisomycin/saline injection after testing for context conditioning, no reminding. B averaged amplitudes (+SEM) of withdrawal responses in three groups of snails measured in two different contexts. Learning & Memory, 2005

Protocol of a context conditioning experiment (A) with anisomycin/saline injection immediately after reminding. B averaged amplitudes (±SEM) of withdrawal responses in three groups of snails measured in two different contexts. MEMORY IS ERASED? ? ?

Nitric oxide (NO) — which is generated principally by NO synthase (NOS) — or higher nitrogen oxides (represented by NOx) can react, in the presence of electron acceptors, with protein thiols to generate Snitrosylated proteins (SNO proteins). In addition, nitrosylation can occur through transnitrosylation involving a nitrosothiol (SNO), such as Snitrosoglutathione

Protein nitrosylation Nitrosylation is a protein modification in which a nitrosyl group is post -translationally added to a protein. S-nitrosylation, discovered by Joseph Loscalzo, is an important biological reaction of nitric oxide; it refers to the conversion of thiol groups, including cysteine residues in proteins, to form Snitrosothiols (RSNOs). S-Nitrosylation is a mechanism for dynamic, post-translational regulation of most or all major classes of protein.

• Known: • Nitric oxide is necessary for synaptic plasticity • NO in small concentrations activates protein synthesis via G-pathways, while in big concentrations LOCALLY impairs proteins functioning via S-nitrosylation mechanism. • Question: • ? NO is necessary both for memory formation and local memory plastification in synapses?

Relearning in rats Test 1 – after FC Test 2 – after feeding in FC context

A Prion-Based Model for Self-Perpetuating Synaptic Change

Thank yo u for attention. I‘m off.