Neuronal circuits in early development

Sensory experience even early in life can shape our brains. For example newborns can recognize their mother’s voice. How does this early experience sculpt the brain? What circuits does experience act on?

To start answering these questions we haver to first identify what neuronal circuits are present in the young brain. It turns out that the young brain is structurally different from the adult brain. For example before and during the critical period a transient neuronal circuit is present in cortex. This circuit is formed by subplate neurons (SP) (reviewed in Kanold 2009, Kanold and Luhmann 2010, Kanold 2019, Kanold et al. 2019). These neurons receive thalamic inputs and our work shows that they provide excitatory input to cortical layer 4 (see figure), the ultimate target of thalamic fibers (Zhao, Kao, Kanold, 2009; Viswanathan et al. 2016, Deng et al. 2017). Thus, subplate neurons form a crucial relay of thalamic activity. We recently showed that this neurons respond to sound stimuli before layer 4 is activated and that a  nascent topographic organization is present within subplate (Wess et al, 2017). Thus early sensory experience has the potential to alter subplate neuron circuits, and possibly set up a template of the future cortical organization.

SP circuits.png

Because after the critical period – when subplate neurons are no longer present – only limited plasticity is present, it is possible that this circuit participates in types of synaptic plasticity that occur only during the critical period. Thus, the disappearance of this circuit might be what ends the critical period.

Our previous work and the work of others showed that loss of subplate neurons during development leads to severe developmental malformations. Without subplate the topographically pattered connections between thalamus and layer 4 do not develop  (Ghosh et al. 1992Kanold et al., Science 2003Tolner et al 2012). Our work points to functional deficits underlying these anatomical malformations. Without subplate neurons the connection between thalamus and layer 4 as well as inhibitory transmission within layer 4 do not mature  (Kanold et al., Science 2003, Kanold & Shatz Neuron  2006Tolner et al 2012). The result is that layer 4 is not driven by thalamic inputs. Given that neural activity is required for synaptic strengthening these functional defects are consistent with the observed anatomical deficits after subplate lesions. Thus one role of subplate is to act as a “teacher” helping thalamic inputs to connect to their targets in layer 4. 

Our current work focuses on revealing these early circuits and on elucidating how these early circuits shape the functional organization of the brain and control the critical period (Zhao et al. 2009, Viswanathan et al 2012, Meng et al 2014, Deng et al. 2017). 

To accomplish our goals we use a multi-faceted approach utilizing neurophysiological (electrophysiology and imaging) and molecular techniques as well as computer simulations of the behavior of single neurons and neuronal networks.

Clinical relevance:

Subplate neurons are present in the human cortex during prenatal and early postnatal times, depending on the region of cortex. In fact in the second trimester a large fraction of cortex is occupied by subplate neurons. Subplate neurons are are highly susceptible to injury, especially in the womb. Short episodes of hypoxia (such as occurring during birth!) selectively damage subplate neurons (see here), and we show that even “mild” injuries cause altered subplate circuits (Sheikh, Meng et al. 2018). Such hypoxic episodes in humans are thought to be related to the development of cerebral palsy and other disabilities many of which are associated with aberrant cortical activity. Similarly our work showed that fetal exposure to VPA, which is linked to the autism in humans (review1, review2, review3), results in altered circuits to subplate neurons in neonatal animals (Nagode et al. 2017). Thus changes in the cortical circuitry in autism are present in the developing cortex from the youngest ages on. 

Since subplate neurons are the first neurons to respond to sensory stimuli (Wess et al. 2017), changes in subplate circuits would result in changed sensory processing and such changes could be used diagnostically.  

Thus learning more about the subplate and its function is important in understanding the origin ofneurodevelopmental diseases (Kanold et al. 2019).