Sensory experience even early in life can shape our brains. For example newborns can recognize their mother’s voice, and many parents play music to their infants, hoping to induce the ‘Mozart effect’. But how does such early sensory experience sculpt the brain? What circuits does experience act on? And why is the effect of this kind of experience seemingly more powerful in early development than later in life?
To answer these questions, we first identify which neuronal circuits are present in the young brain, determine the function of each circuit, and test how experience acts on them.
A transient circuit in the developing cortex
It turns out that the young brain is structurally different from the adult brain (Chang and Kanold 2021). For example before and during the critical period a transient neuronal circuit is present in cortex. This circuit is formed by subplate neurons (reviewed in Kanold 2009, Kanold and Luhmann 2010, Kanold et al. 2019, Molnar, Luhmann, Kanold 2020). Subplate neurons were first described by Kostovic and Molliver at JHU in 1974 and turn out to be among the first generated neurons in the cortex. Interestingly, and in contrast to other cortical neurons, most subplate neurons disappear over development (Kostovic and Rakic 1984, Luskin and Shatz 1985).
Subplate neurons as early thalamic relays and proto-map
However, in early development subplate neurons receive thalamic as well as cortical inputs and our work shows that they provide excitatory input to cortical layer 4 (see figure), the ultimate target of thalamic fibers (Hermann & Shatz 1994, Friauf & Shatz 1990, Friauf & Shatz 1991, Zhao, Kao, Kanold 2009, Viswanathan et al. 2016, Deng et al. 2017). Thus, subplate neurons form a crucial relay of thalamic activity. We showed that these early thalamic connections transmit sensory information by demonstrating that subplate neurons respond to sound stimuli before layer 4 is activated (Wess et al. Proceedings of the National Academy 2017). We also showed that a nascent topographic organization is present within subplate (Wess et al. Proceedings of the National Academy 2017). Thus, there is an early ‘proto-organizational’ period where a rough sketch of cortical organization is laid out in subplate.
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, or remodeling, of this circuit might trigger the end of the critical period.
Subplate circuits are sculpted by early sensory experience
Since subplate neurons are the first neurons to respond to sensory stimuli (Wess et al. Proceedings of the National Academy 2017), they also can be influenced by sensory experience. We showed that altered auditory experience can alter subplate circuits before thalamic fibers activate layer 4 (Meng et al. Science Advances 2021, Mukherjee et al. Cerebral Cortex 2021). These findings suggest that subplate neurons are the earliest cortical substrate of experience-dependent plasticity. This is important because most prior studies of experience dependent plasticity timed sensory manipulations based on events in layer 4 and thus have changed experience too late to alter subplate neurons.
Subplate loss or injury alters cortical development
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 patterned connections between thalamus and layer 4 do not develop (Ghosh et al. 1992, Kanold et al. Science 2003, Tolner 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 2006, Tolner 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.
Current directions
Given that subplate circuits are shaped by sensory experience, we are investigating what the nature of this experience is and how such experience shapes the functional organization of subplate and the other layers of the auditory cortex.
Clinical relevance
Subplate neurons are present in the human cortex. In fact, in the second trimester a large fraction of cortex is occupied by subplate. Subplate neurons are highly susceptible to injury, especially in the womb. Short episodes of hypoxia (such as occurring during birth!) can 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. Similarly our work showed that fetal exposure to valproic acid (VPA), which is linked to autism in humans, results in altered circuits to subplate neurons in neonatal animals (Nagode et al. 2017). Thus, changes in the subplate circuitry and neurodevelopment disorders appear to be linked, but fully understanding this connection will take require substantial further work.
Moreover, since subplate neurons are the first neurons to respond to sensory stimuli (Wess et al. Proceedings of the National Academy 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 of neurodevelopmental disorders (Luhmann, Kanold, Molnar, Vanhatalo 2022).
Key publications:
X. Meng*, D. Mukherjee*, J.P-Y Kao, P.O. Kanold, “Early peripheral activity alters nascent subplate circuits in the auditory cortex” Science Advances 2021
Z. Molnar, H. Luhmann, P.O. Kanold, “Transient cortical circuits match spontaneous and sensory-driven activity during development”, Science 2020
A. Sheikh*, X. Meng*, J. Liu, A. Mikhailova, JPY. Kao, P. S. McQuillen, P. O. Kanold, “Neonatal Hypoxia-Ischemia Causes Functional Circuit Changes in Subplate Neurons”, Cerebral Cortex 2018 (Aminah’s Cover)
J.M. Wess, A.Isaiah, P.W. Watkins, P. O. Kanold, “Subplate neurons are the first cortical neurons to respond to sensory stimuli”, Proceedings of the National Academy of Sciences 2017
C. Zhao, JPY Kao, P.O. Kanold,”Functional microcircuits in neonatal cortex connect thalamus and layer 4″, Journal of Neuroscience, 29(49):15479-88, 2009.
P.O. Kanold, P. Kara, R.C. Reid, C.J. Shatz, ” Role of Subplate Neurons in Functional Maturation of Visual Cortical Columns “, Science 2003
