Brain-derived neurotrophic factor: a bridge between inflammation and neuroplasticity

You'll have to ask your doctor exactly what protocol they have for you to have the best neuroplasticity and neurogenesis.
http://journal.frontiersin.org/Journal/10.3389/fncel.2014.00430/full?
Francesca Calabrese¹, Andrea C. Rossetti¹, Giorgio Racagni¹, Peter Gass², Marco A. Riva¹ and Raffaella Molteni^1*

• ¹Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy
• ²Department of Psychiatry and Psychotherapy, Research Group Animal Models in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Mannheim, Germany

Cytokines are key regulatory mediators involved in the host response to immunological challenges, but also play a critical role in the communication between the immune and the central nervous system. For this, their expression in both systems is under a tight regulatory control. However, pathological conditions may lead to an overproduction of pro-inflammatory cytokines that may have a detrimental impact on central nervous system. In particular, they may damage neuronal structure and function leading to deficits of neuroplasticity, the ability of nervous system to perceive, respond and adapt to external or internal stimuli. In search of the mechanisms by which pro-inflammatory cytokines may affect this crucial brain capability, we will discuss one of the most interesting hypotheses: the involvement of the neurotrophin brain-derived neurotrophic factor (BDNF), which represents one of the major mediators of neuroplasticity.

Neuroplasticity and Brain-Derived Neurotrophic Factor

For many years the medical field held the belief that the brain did not make major changes after a certain point in time. It was fixed or set on a specific path. Today, in contrast, we know that the brain is actually capable of changing and developing throughout a lifetime. It is plastic or malleable, and the term neuroplasticity is used to describe this tendency for the brain to keep developing, changing, and potentially healing itself.

Specifically, neuroplasticity or neuronal plasticity refers to the ability of the nervous system to respond and adapt to environmental challenges and encompasses a series of functional and structural mechanisms that may lead to neuronal remodeling, formation of novel synapses and birth of new neurons. Neuronal plasticity is intimately linked to cellular responsiveness and may therefore be considered an index of the neuronal capability to adapt its function to a different demand. Failure of such mechanisms might enhance the susceptibility to environmental challenges, such as stress, and ultimately lead to psychopathology.

Among the genes responsive to neuronal activity, neurotrophic factors (NTFs), and in particular the neurotrophin family, play an important role. In fact, besides their classical role in supporting neuronal survival, NTFs finely modulate all the crucial steps of network construction, from neuronal migration to experience-dependent refinement of local connections (Poo, 2001). These functions were first reported based on the observation that, during the development of the nervous system, neuron survival depends on the limited amount of specific NTFs secreted by target cells (Huang and Reichardt, 2001). However, it is now well established that NTFs are important mediators of neuronal plasticity also in adulthood where they modulate axonal and dendritic growth and remodeling, membrane receptor trafficking, neurotransmitter release, synapse formation and function (Lu et al., 2005). The neurotrophin brain-derived neurotrophic factor (BDNF) has emerged as crucial mediator of neuronal plasticity, since it is abundant in brain regions particularly relevant for plasticity, but also because it shows a remarkable activity-dependent regulation of expression and secretion (Bramham and Messaoudi, 2005), suggesting that it might indeed bridge experience with enduring change in neuronal function. BDNF has a complex genomic structure, which results into a sophisticated organization in terms of transcriptional, translational and post-translational regulatory mechanisms (Aid et al., 2007). In particular, the rat BDNF gene—that is similar to the human gene—can generate nine distinct transcripts through the alternative splicing of 5’ un-translated exons to a common 3’ exon (IX), which encodes the BDNF protein (Aid et al., 2007). These transcripts have different distribution and/or translation efficacy and, more importantly, may sub-serve different functions. For example, transcripts that are primarily localized or targeted to dendrites may sustain local neurotrophin production, thus providing an effective mechanism to regulate synaptic structure and function (An et al., 2008; Wu et al., 2011). Since the transcription of the different isoforms is regulated by specific signaling pathways (Pruunsild et al., 2011), their investigation may provide useful information on the up-stream mechanisms contributing to the changes of BDNF gene expression.

The mechanisms that lie downstream from NTFs and contribute to the maintenance of neuroplasticity are different i.e., adult neurogenesis and neuronal remodeling, but on the purpose of this mini-review we will focus only on adult neurogenesis, the process by which neurons are generated. Neurogenesis occurs under precise spatial and temporal control, but it can be modulated by both internal and external stimuli. Among these, several sources of data indicate the positive impact of BDNF on adult neurogenesis (Lee et al., 2002; Sairanen et al., 2005; Scharfman et al., 2005; Gass and Riva, 2007; Bergami et al., 2008; Chan et al., 2008; Li et al., 2008; Waterhouse et al., 2012), however in this review we will focus our attention on the effects of pro-inflammatory cytokines.